rs104894683

Variant names:

• chr19-46755685-G-A
• rs104894683
• NM_024301.5:c.235G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-46755685-G-A
• chr19-46755685-G-C
• chr19-46755685-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_024301.5(FKRP):​c.235G>A​(p.Val79Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,590,552 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V79A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:13
• Conservation: PhyloP100: 1.83
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.8498 (below the threshold of 3.09). Trascript score misZ: -2.4986 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, muscular dystrophy-dystroglycanopathy, type A, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.017470866).
• BP6: Variant 19-46755685-G-A is Benign according to our data. Variant chr19-46755685-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4229.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00398 (606/152318) while in subpopulation AFR AF = 0.0139 (578/41584). AF 95% confidence interval is 0.013. There are 3 homozygotes in GnomAd4. There are 290 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024301.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	NM_024301.5	MANE Select	c.235G>A	p.Val79Met	missense	Exon 4 of 4	NP_077277.1
	FKRP	NM_001039885.3		c.235G>A	p.Val79Met	missense	Exon 4 of 4	NP_001034974.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKRP	ENST00000318584.10	TSL:1 MANE Select	c.235G>A	p.Val79Met	missense	Exon 4 of 4	ENSP00000326570.4
	FKRP	ENST00000594467.5	TSL:4	c.-195G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000471971.1
	FKRP	ENST00000391909.7	TSL:2	c.235G>A	p.Val79Met	missense	Exon 4 of 4	ENSP00000375776.2

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 600 AN: 152200 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00103 AC: 222 AN: 215090 AF XY: 0.000872

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000510

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000205

Gnomad OTH exome AF: 0.000364

GnomAD4 exome AF: 0.000429 AC: 617 AN: 1438234 Hom.: 0 Cov.: 33 AF XY: 0.000370 AC XY: 265 AN XY: 715266

African (AFR) AF: 0.0153 AC: 507 AN: 33092

American (AMR) AF: 0.000567 AC: 25 AN: 44086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 38884

South Asian (SAS) AF: 0.0000710 AC: 6 AN: 84546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39150

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5748

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1107096

Other (OTH) AF: 0.00105 AC: 63 AN: 59786

GnomAD4 genome AF: 0.00398 AC: 606 AN: 152318 Hom.: 3 Cov.: 33 AF XY: 0.00389 AC XY: 290 AN XY: 74492

African (AFR) AF: 0.0139 AC: 578 AN: 41584

American (AMR) AF: 0.00105 AC: 16 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00169 Hom.: 2

Bravo AF: 0.00438

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00117 AC: 141

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:6

Dec 31, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 28, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FKRP c.235G>A (p.Val79Met) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00077 in 1590552 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 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 a benign polymorphism found primarily in populations of African or African-American origin. ClinVar contains an entry for this variant (Variation ID: 4229). Based on the evidence outlined above, the variant was classified as likely benign.

Apr 12, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 23, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FKRP c.235G>A; p.Val79Met variant (rs104894683) is reported in several individuals affected with limb girdle muscular dystrophy (de Paula 2003), including three siblings that carried the p.Val79Met variant in trans to a nonsense variant (Vieira 2006). Of the three siblings, two were severely affected and also carried a p.Pro89Ala variant, which was not identified in the third mildly affected sibling (Vieira 2006). The p.Val79Met variant is reported in ClinVar (Variation ID: 4229) and is found in the African population with an overall allele frequency of 1.5% (320/21382 alleles, including one homozygote) in the Genome Aggregation Database. The valine at codon 79 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the p.Val79Met variant is uncertain at this time. References: de Paula F et al. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet. 2003 Dec;11(12):923-30. Vieira NM et al. Mutation analysis in the FKRP gene provides an explanation for a rare cause of intrafamilial clinical variability in LGMD2I. Neuromuscul Disord. 2006 Dec;16(12):870-3.

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1;BP6

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 20, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:4

Feb 17, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22995991, 18645206, 17113772, 14647208, 25898921)

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FKRP: BS1, BS2

May 03, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:1 Benign:1

Jan 10, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Cardiovascular phenotype Benign:1

Mar 20, 2019

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.017	T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.1	L
PhyloP100		1.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.057	T
Polyphen		0.89	P
Vest4		0.68
MVP		0.63
MPC		1.0
ClinPred		0.010	T
GERP RS		2.6
Varity_R		0.17
gMVP		0.67
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs104894683; hg19: chr19-47258942;