chr19-46755877-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024301.5(FKRP):​c.427C>A​(p.Arg143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00524 in 1,493,634 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0054 ( 30 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

4
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.56
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009333223).
BP6
Variant 19-46755877-C-A is Benign according to our data. Variant chr19-46755877-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 129057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755877-C-A is described in Lovd as [Pathogenic]. Variant chr19-46755877-C-A is described in Lovd as [Likely_benign]. Variant chr19-46755877-C-A is described in Lovd as [Benign]. Variant chr19-46755877-C-A is described in Lovd as [Likely_pathogenic].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00362 (551/152318) while in subpopulation NFE AF= 0.00609 (414/68012). AF 95% confidence interval is 0.0056. There are 1 homozygotes in gnomad4. There are 250 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FKRPNM_024301.5 linkc.427C>A p.Arg143Ser missense_variant Exon 4 of 4 ENST00000318584.10 NP_077277.1 Q9H9S5A0A024R0R7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FKRPENST00000318584.10 linkc.427C>A p.Arg143Ser missense_variant Exon 4 of 4 1 NM_024301.5 ENSP00000326570.4 Q9H9S5

Frequencies

GnomAD3 genomes
AF:
0.00363
AC:
552
AN:
152204
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00101
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00353
Gnomad ASJ
AF:
0.00317
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00434
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00610
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00448
AC:
445
AN:
99432
Hom.:
5
AF XY:
0.00418
AC XY:
227
AN XY:
54344
show subpopulations
Gnomad AFR exome
AF:
0.000893
Gnomad AMR exome
AF:
0.00501
Gnomad ASJ exome
AF:
0.00342
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00363
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00661
Gnomad OTH exome
AF:
0.00730
GnomAD4 exome
AF:
0.00542
AC:
7272
AN:
1341316
Hom.:
30
Cov.:
32
AF XY:
0.00540
AC XY:
3552
AN XY:
657222
show subpopulations
Gnomad4 AFR exome
AF:
0.000995
Gnomad4 AMR exome
AF:
0.00535
Gnomad4 ASJ exome
AF:
0.00278
Gnomad4 EAS exome
AF:
0.0000286
Gnomad4 SAS exome
AF:
0.00478
Gnomad4 FIN exome
AF:
0.000336
Gnomad4 NFE exome
AF:
0.00597
Gnomad4 OTH exome
AF:
0.00551
GnomAD4 genome
AF:
0.00362
AC:
551
AN:
152318
Hom.:
1
Cov.:
33
AF XY:
0.00336
AC XY:
250
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.00101
Gnomad4 AMR
AF:
0.00353
Gnomad4 ASJ
AF:
0.00317
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00434
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.00609
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00450
Hom.:
0
Bravo
AF:
0.00405
TwinsUK
AF:
0.00431
AC:
16
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.00106
AC:
4
ESP6500EA
AF:
0.00491
AC:
37
ExAC
AF:
0.00190
AC:
177
Asia WGS
AF:
0.000868
AC:
3
AN:
3470

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Nov 08, 2023
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 22, 2014
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 17, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 29, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: FKRP c.427C>A (p.Arg143Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 1493634 control chromosomes in the gnomAD database (v4.0.0), including 31 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0024), strongly suggesting that the variant is benign. c.427C>A has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Sframeli_2017, Brockington_2001). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28688748, 11741828). ClinVar contains an entry for this variant (Variation ID: 129057). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:4
Nov 22, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 09, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11741828, 16344347, 22451200, 16717227, 18832576, 27884173, 29065428, 28482373, 32403337) -

Mar 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

FKRP: BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Autosomal recessive limb-girdle muscular dystrophy type 2I Benign:3
Jan 30, 2018
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 08, 2019
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
Apr 13, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy Benign:1
May 14, 2019
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Dec 26, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely 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 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.043
T
BayesDel_noAF
Pathogenic
0.17
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.40
.;T;T
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.66
T;.;T
MetaRNN
Benign
0.0093
T;T;T
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Benign
1.4
.;L;L
PrimateAI
Pathogenic
0.80
T
PROVEAN
Benign
-1.8
.;N;N
REVEL
Pathogenic
0.69
Sift
Benign
0.58
.;T;T
Sift4G
Benign
0.085
T;T;T
Polyphen
0.18
.;B;B
Vest4
0.58, 0.58
MVP
0.98
MPC
0.83
ClinPred
0.0045
T
GERP RS
3.6
Varity_R
0.59
gMVP
0.79

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.

Other links and lift over

dbSNP: rs148206382; hg19: chr19-47259134; COSMIC: COSV105190863; COSMIC: COSV105190863; API