19-46756004-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024301.5(FKRP):c.554C>T(p.Ala185Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,556,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A185A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.03

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29710004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5	c.554C>T	p.Ala185Val	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.554C>T	p.Ala185Val	missense_variant	4/4	1	NM_024301.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151886 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1405052 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 696196

Gnomad4 AFR exome AF: 0.0000314

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 AF: 0.0000132 AC: 2 AN: 151886 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74190

Gnomad4 AFR AF: 0.0000483

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 01, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2022

The p.A185V variant (also known as c.554C>T), located in coding exon 1 of the FKRP gene, results from a C to T substitution at nucleotide position 554. The alanine at codon 185 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. 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

Invitae

Jul 19, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 185 of the FKRP protein (p.Ala185Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 528812). 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	0.11
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.31	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.062	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0070	B;B
Vest4		0.26
MutPred		0.28		Loss of glycosylation at P186 (P = 0.0874);Loss of glycosylation at P186 (P = 0.0874);
MVP		0.88
MPC		0.67
ClinPred		0.14	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.66

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: rs1032563159; hg19: chr19-47259261;