rs104894682

Positions:

chr19-46756936-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong

The ENST00000318584.10(FKRP):c.1486T>A(p.Ter496ArgextTer21) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FKRP
ENST00000318584.10 stop_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.85

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Stoplost variant in ENST00000318584.10 Downstream stopcodon found after 590 codons.

PP5

Variant 19-46756936-T-A is Pathogenic according to our data. Variant chr19-46756936-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756936-T-A is described in Lovd as [Pathogenic]. Variant chr19-46756936-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.1486T>A	p.Ter496ArgextTer21	stop_lost	4/4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
FKRP	ENST00000318584.10 linkuse as main transcript	c.1486T>A	p.Ter496ArgextTer21	stop_lost	4/4	1	NM_024301.5	ENSP00000326570	P1
FKRP	ENST00000391909.7 linkuse as main transcript	c.1486T>A	p.Ter496ArgextTer21	stop_lost	4/4	2		ENSP00000375776	P1
FKRP	ENST00000597339.5 linkuse as main transcript	n.247-4897T>A		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5 linkuse as main transcript	n.247+8271T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000813

AC:

AN:

245964

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134250

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460586

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2I

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 22, 2003	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 09, 2020	- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 01, 2022

Variant summary: FKRP c.1486T>A (p.X496ArgextX21) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. The variant allele was found at a frequency of 8.1e-06 in 245964 control chromosomes (gnomAD). c.1486T>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy and vacuolar myopathy (examples: Driss_2003, Kefi_2008, Mair_2020, Walter_FKRP_2004). The variant also seggregated with disease. These data indicate that the variant is very likely to be associated with disease. Driss_2003 demonstrated that this variant reduced alpha dystroglycan and laminin levels in isolated muscle protein immmunoblots. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=4) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Muscular dystrophy-dystroglycanopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 13, 2017

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 25, 2017

- -

Walker-Warburg congenital muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change disrupts the translational stop signal of the FKRP mRNA. It is expected to extend the length of the FKRP protein by 21 additional amino acid residues. This variant is present in population databases (rs104894682, gnomAD 0.0009%). This protein extension has been observed in individuals with limb girdle muscular dystrophy (PMID: 10838249, 12707439, 15060126, 18671187). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4223). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.89

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

3.2e-12

A;A

Vest4

0.079

GERP RS

5.1

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