chr19-46755699-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_024301.5(FKRP):c.249C>T(p.Ala83Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,582,434 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 16 hom., cov: 33)

Exomes 𝑓: 0.013 ( 158 hom. )

Consequence

FKRP
NM_024301.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -2.99

Publications

6 publications found

Variant links:

Genes affected

FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

FKRP Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy type 2I
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics
muscular dystrophy-dystroglycanopathy type B5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
myopathy caused by variation in FKRP
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
congenital muscular dystrophy with cerebellar involvement
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy with intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy without intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscle-eye-brain disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscular dystrophy-dystroglycanopathy, type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FKRP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 19-46755699-C-T is Benign according to our data. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755699-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 96107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.99 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00925 (1409/152330) while in subpopulation SAS AF = 0.0186 (90/4828). AF 95% confidence interval is 0.0155. There are 16 homozygotes in GnomAd4. There are 697 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.249C>T	p.Ala83Ala	synonymous_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10 link	c.249C>T	p.Ala83Ala	synonymous_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4		Q9H9S5

Frequencies

GnomAD3 genomes

AF:

0.00929

AC:

1414

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0192

Gnomad FIN

AF:

0.0156

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.0107

AC:

2147

AN:

200206

AF XY:

0.0118

show subpopulations

Gnomad AFR exome

AF:

0.00247

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.0119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0149

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.0133

AC:

19023

AN:

1430104

Hom.:

158

Cov.:

AF XY:

0.0136

AC XY:

9678

AN XY:

710616

show subpopulations

African (AFR)

AF:

0.00222

AC:

AN:

32878

American (AMR)

AF:

0.00230

AC:

100

AN:

43570

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

298

AN:

25678

East Asian (EAS)

AF:

0.0000261

AC:

AN:

38344

South Asian (SAS)

AF:

0.0179

AC:

1500

AN:

83892

European-Finnish (FIN)

AF:

0.0136

AC:

513

AN:

37806

Middle Eastern (MID)

AF:

0.0195

AC:

112

AN:

5734

European-Non Finnish (NFE)

AF:

0.0143

AC:

15780

AN:

1102844

Other (OTH)

AF:

0.0109

AC:

646

AN:

59358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1180

2359

3539

4718

5898

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

592

1184

1776

2368

2960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00925

AC:

1409

AN:

152330

Hom.:

Cov.:

AF XY:

0.00936

AC XY:

697

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00252

AC:

105

AN:

41588

American (AMR)

AF:

0.00405

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0186

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0156

AC:

166

AN:

10628

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0135

AC:

921

AN:

68008

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

153

230

306

383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0118

Hom.:

Bravo

AF:

0.00767

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala83Ala in exon 4 of FKRP: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1.3% (115/8570) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs149030303). -

May 12, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 15, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 30, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

Benign:1

Aug 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 25, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Walker-Warburg congenital muscular dystrophy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

1.7

(source)

DANN

Benign

0.92

PhyloP100

-3.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over