rs759539583

Positions:

• chr19-46755633-C-G
• chr19-46755633-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_024301.5(FKRP):​c.183C>G​(p.Asn61Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.290

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_024301.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5	c.183C>G	p.Asn61Lys	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.183C>G	p.Asn61Lys	missense_variant	4/4	1	NM_024301.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Walker-Warburg congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 12, 2021

This sequence change replaces asparagine with lysine at codon 61 of the FKRP protein (p.Asn61Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of FKRP-related conditions (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;.;.;D;.;.;.;.;.;.;.;.;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;.;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	.;L;.;.;L;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	.;D;.;.;D;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0070	.;D;.;.;D;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;T;D;D;T;D;D;D;D;D;D;D;D;D
Polyphen		0.89	.;P;.;.;P;.;.;.;.;.;.;.;.;.
Vest4		0.58, 0.61
MutPred		0.28		Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);Gain of ubiquitination at N61 (P = 0.0211);
MVP		0.99
MPC		0.99
ClinPred		0.94	D
GERP RS		2.5
Varity_R		0.69
gMVP		0.93

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: rs759539583; hg19: chr19-47258890;