Variant rs886042506 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024301.5(FKRP):c.162_165dupGGAG(p.Phe56GlyfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000237 in 1,604,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

FKRP
NM_024301.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.25

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 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 170 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-46755610-C-CGGGA is Pathogenic according to our data. Variant chr19-46755610-C-CGGGA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 282866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.162_165dupGGAG	p.Phe56GlyfsTer6	frameshift_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10 link	c.162_165dupGGAG	p.Phe56GlyfsTer6	frameshift_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4		Q9H9S5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000862

AC:

AN:

232120

Hom.:

AF XY:

0.00

AC XY:

AN XY:

126546

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:

0.0000191

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1452756

Hom.:

Cov.:

AF XY:

0.0000263

AC XY:

AN XY:

722400

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.0000279

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 24, 2022	The FKRP c.162_165dup; p.Phe56GlyfsTer6 variant (rs886042506; also reported as 165InsGGAG; ClinVar Variation ID: 282866), has been previously identified in trans with other pathogenic variants in FKRP in at least two patients with symptoms of congenital muscular dystrophy and reduced glycosylated alpha-dystroglycan (Brockington 2001 and Peat 2008). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last (and only coding) exon of the FKRP gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 6 amino acid residues not usually present. Additionally, several downstream truncating variants have been described in individuals with FKRP-related muscular dystrophy and are considered pathogenic (Selected references: Brockington 2001 and Matsumoto 2005). Based on the available information, the p.Phe56GlyfsTer6 variant is considered pathogenic. References: Brockington M et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet. 2001 Dec;69(6):1198-209. PMID: 11592034 Matsumoto H et al. Congenital muscular dystrophy with glycosylation defects of alpha-dystroglycan in Japan. Neuromuscul Disord. 2005 May;15(5):342-8. PMID: 15833426. Peat RA et al. Diagnosis and etiology of congenital muscular dystrophy. Neurology. 2008 Jul 29;71(5):312-21. PMID: 18160674. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 21, 2023	PM2, PS4_moderate, PVS1 -

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

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	FKRP NM_024301.4 ex 4 p.Phe56Glyfs*6 (c.162_165dup): This variant has been reported in the literature in at least one individual with autosomal congenital muscular dystrophy (Brockington 2001 PMID:11592034). This variant is present in 0.001% (2/104602) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-47258867-C-CGGGA) and is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:282866). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 6 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene (Thornhill 2008 PMID:18477595). In summary, this variant is classified as pathogenic based on the data above. -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 01, 2017

- -

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

Aug 09, 2024

Variant summary: FKRP c.162_165dupGGAG (p.Phe56GlyfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.6e-06 in 232120 control chromosomes. c.162_165dupGGAG has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. Additionally, variants downstream of this position have been classified as pathogenic by our lab. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 282866). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 31, 2023

- -

Walker-Warburg congenital muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2024

This sequence change creates a premature translational stop signal (p.Phe56Glyfs*6) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 440 amino acid(s) of the FKRP protein. This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with FKRP-related conditions (PMID: 11592034, 18160674). ClinVar contains an entry for this variant (Variation ID: 282866). This variant disrupts a region of the FKRP protein in which other variant(s) (p.Q460*) have been determined to be pathogenic (PMID: 16476814; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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