19-46756651-G-A

Position:

• chr19-46756651-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024301.5(FKRP):​c.1201G>A​(p.Asp401Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.70

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5	c.1201G>A	p.Asp401Asn	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.1201G>A	p.Asp401Asn	missense_variant	4/4	1	NM_024301.5	ENSP00000326570.4
FKRP	ENST00000391909.7	c.1201G>A	p.Asp401Asn	missense_variant	4/4	2		ENSP00000375776.2
FKRP	ENST00000597339.5	n.247-5182G>A		intron_variant		5
FKRP	ENST00000600646.5	n.247+7986G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461090 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 726794

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: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 08, 2017

- -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 08, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2023

The p.D401N variant (also known as c.1201G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 1201. The aspartic acid at codon 401 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in the heterozygous state in an individual with congenital muscular dystrophy (Brockington M et al. Am J Hum Genet, 2001 Dec;69:1198-209). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Walker-Warburg congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

This missense change has been observed in individual(s) with clinical features of FKRP-related conditions (PMID: 11592034, 17351538, 19917824). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FKRP protein function. ClinVar contains an entry for this variant (Variation ID: 551029). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 401 of the FKRP protein (p.Asp401Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.63
Sift	Benign	0.14	T;T
Sift4G	Benign	0.16	T;T
Polyphen		1.0	D;D
Vest4		0.50
MutPred		0.56		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.98
MPC		1.6
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.31
gMVP		0.76

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: rs1555739117; hg19: chr19-47259908; COSMIC: COSV59359299; COSMIC: COSV59359299;