19-46756814-C-A

Position:

• chr19-46756814-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_024301.5(FKRP):​c.1364C>A​(p.Ala455Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 4.85

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 19-46756814-C-A is Pathogenic according to our data. Variant chr19-46756814-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 4226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756814-C-A is described in Lovd as [Pathogenic]. Variant chr19-46756814-C-A is described in Lovd as [Pathogenic]. Variant chr19-46756814-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5	c.1364C>A	p.Ala455Asp	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	c.1364C>A	p.Ala455Asp	missense_variant	4/4	1	NM_024301.5	ENSP00000326570.4
FKRP	ENST00000391909.7	c.1364C>A	p.Ala455Asp	missense_variant	4/4	2		ENSP00000375776.2
FKRP	ENST00000597339.5	n.247-5019C>A		intron_variant		5
FKRP	ENST00000600646.5	n.247+8149C>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447190 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 718928

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 03, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33101984, 31130284, 31268217, 16368217, 28454995, 14652796, 22908982, 23420653, 15574464, 23894383, 18671187, 19955119) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2017	- -

Muscular dystrophy-dystroglycanopathy type B5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2004	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 04, 2023

- -

Walker-Warburg congenital muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FKRP function (PMID: 15574464, 19955119). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FKRP protein function. ClinVar contains an entry for this variant (Variation ID: 4226). This missense change has been observed in individuals with congenital muscular dystrophy, limb-girdle muscular dystrophy and muscle-eye brain disease (PMID: 14652796, 16368217, 18671187, 23420653, 23894383). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 455 of the FKRP protein (p.Ala455Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	.;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.99	D;D
Vest4		0.75
MutPred		0.60		Gain of relative solvent accessibility (P = 0.0217);Gain of relative solvent accessibility (P = 0.0217);
MVP		0.99
MPC		1.9
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.82
gMVP		0.80

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

Other links and lift over

dbSNP: rs28937903; hg19: chr19-47260071;