19-46756378-G-C

Position:

• chr19-46756378-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_024301.5(FKRP):​c.928G>C​(p.Glu310Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,411,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E310K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.518

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 2 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_024301.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.120173395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5	c.928G>C	p.Glu310Gln	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.928G>C	p.Glu310Gln	missense_variant	4/4	1	NM_024301.5	P1
FKRP	ENST00000391909.7	c.928G>C	p.Glu310Gln	missense_variant	4/4	2		P1
FKRP	ENST00000597339.5	n.247-5455G>C		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5	n.247+7713G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000439 AC: 7 AN: 159598 Hom.: 0 AF XY: 0.0000572 AC XY: 5 AN XY: 87410

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000253

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 18 AN: 1411748 Hom.: 0 Cov.: 32 AF XY: 0.0000186 AC XY: 13 AN XY: 697914

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.0000212

Gnomad4 NFE exome AF: 9.19e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000268 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Oct 14, 2021

- -

Walker-Warburg congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 20, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 310 of the FKRP protein (p.Glu310Gln). This variant is present in population databases (rs765885747, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with FKRP-related conditions. ClinVar contains an entry for this variant (Variation ID: 1401035). 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. 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	Benign	0.099
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.58
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.81	.;T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.060	N;N
MutationTaster	Benign	0.96	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.45	N;N
REVEL	Benign	0.16
Sift	Benign	0.42	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.013	B;B
Vest4		0.055
MutPred		0.24		Loss of phosphorylation at T314 (P = 0.1863);Loss of phosphorylation at T314 (P = 0.1863);
MVP		0.87
MPC		0.64
ClinPred		0.012	T
GERP RS		4.2
Varity_R		0.30
gMVP		0.74

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: rs765885747; hg19: chr19-47259635;