19-46755585-C-T

Position:

chr19-46755585-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024301.5(FKRP):c.135C>T(p.Ala45=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,604,888 control chromosomes in the GnomAD database, including 16,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1588 hom., cov: 33)

Exomes 𝑓: 0.14 ( 15045 hom. )

Consequence

FKRP
NM_024301.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.496

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 19-46755585-C-T is Benign according to our data. Variant chr19-46755585-C-T is described in ClinVar as [Benign]. Clinvar id is 96105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755585-C-T is described in Lovd as [Benign]. Variant chr19-46755585-C-T is described in Lovd as [Pathogenic]. Variant chr19-46755585-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.496 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.135C>T	p.Ala45=	synonymous_variant	4/4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10 linkuse as main transcript	c.135C>T	p.Ala45=	synonymous_variant	4/4	1	NM_024301.5	ENSP00000326570	P1

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21466

AN:

152140

Hom.:

1583

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.126

Gnomad EAS

AF:

0.128

Gnomad SAS

AF:

0.177

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.142

AC:

32843

AN:

230836

Hom.:

2335

AF XY:

0.143

AC XY:

18006

AN XY:

125774

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.130

Gnomad SAS exome

AF:

0.172

Gnomad FIN exome

AF:

0.117

Gnomad NFE exome

AF:

0.140

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.143

AC:

208019

AN:

1452630

Hom.:

15045

Cov.:

AF XY:

0.144

AC XY:

103902

AN XY:

722134

show subpopulations

Gnomad4 AFR exome

AF:

0.151

Gnomad4 AMR exome

AF:

0.144

Gnomad4 ASJ exome

AF:

0.126

Gnomad4 EAS exome

AF:

0.116

Gnomad4 SAS exome

AF:

0.174

Gnomad4 FIN exome

AF:

0.118

Gnomad4 NFE exome

AF:

0.144

Gnomad4 OTH exome

AF:

0.139

GnomAD4 genome

AF:

0.141

AC:

21484

AN:

152258

Hom.:

1588

Cov.:

AF XY:

0.138

AC XY:

10281

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.151

Gnomad4 AMR

AF:

0.128

Gnomad4 ASJ

AF:

0.126

Gnomad4 EAS

AF:

0.128

Gnomad4 SAS

AF:

0.176

Gnomad4 FIN

AF:

0.125

Gnomad4 NFE

AF:

0.142

Gnomad4 OTH

AF:

0.128

Alfa

AF:

0.138

Hom.:

609

Bravo

AF:

0.143

Asia WGS

AF:

0.158

AC:

549

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ala45Ala 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 14.2% (625/4398) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs2287717). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 11, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -

Muscular dystrophy-dystroglycanopathy type B5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Dystrophin deficiency

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.3

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over