chr19-46755970-A-T

Position:

chr19-46755970-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000318584.10(FKRP):c.520A>T(p.Ser174Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,539,596 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S174S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 26 hom. )

Consequence

FKRP
ENST00000318584.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.74

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 -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in ENST00000318584.10

BP4

Computational evidence support a benign effect (MetaRNN=0.009832382).

BP6

Variant 19-46755970-A-T is Benign according to our data. Variant chr19-46755970-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 96110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755970-A-T is described in Lovd as [Pathogenic]. Variant chr19-46755970-A-T is described in Lovd as [Likely_benign]. Variant chr19-46755970-A-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00154 (234/152222) while in subpopulation SAS AF= 0.019 (92/4830). AF 95% confidence interval is 0.0159. There are 3 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.520A>T	p.Ser174Cys	missense_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.520A>T	p.Ser174Cys	missense_variant	4/4	1	NM_024301.5	ENSP00000326570	P1

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

236

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.0194

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00356

AC:

482

AN:

135390

Hom.:

AF XY:

0.00449

AC XY:

335

AN XY:

74672

show subpopulations

Gnomad AFR exome

AF:

0.000313

Gnomad AMR exome

AF:

0.000608

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00332

Gnomad SAS exome

AF:

0.0145

Gnomad FIN exome

AF:

0.000160

Gnomad NFE exome

AF:

0.00165

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.00232

AC:

3215

AN:

1387374

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

1831

AN XY:

685494

show subpopulations

Gnomad4 AFR exome

AF:

0.000159

Gnomad4 AMR exome

AF:

0.000639

Gnomad4 ASJ exome

AF:

0.000997

Gnomad4 EAS exome

AF:

0.00108

Gnomad4 SAS exome

AF:

0.0144

Gnomad4 FIN exome

AF:

0.000203

Gnomad4 NFE exome

AF:

0.00168

Gnomad4 OTH exome

AF:

0.00262

GnomAD4 genome

AF:

0.00154

AC:

234

AN:

152222

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

130

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00213

Gnomad4 SAS

AF:

0.0190

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00140

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000575

Hom.:

Bravo

AF:

0.00111

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000926

AC:

ExAC

AF:

0.00239

AC:

257

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2016	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	Eurofins Ntd Llc (ga)	Mar 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 26, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	FKRP: PP3, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2018	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 10, 2020

- -

Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 10, 2019

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2019

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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.53

D;D;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

.;T;T

MetaRNN

Benign

0.0098

T;T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

0.34

N;N;.

MutationTaster

Benign

0.90

D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-2.6

D;D;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.020

D;D;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.0

B;B;.

Vest4

0.49

MVP

0.84

MPC

1.3

ClinPred

0.028

GERP RS

3.5

Varity_R

0.49

gMVP

0.71

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

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