19-46756082-C-T

Variant names:

• chr19-46756082-C-T
• rs750041378
• NM_024301.5:c.632C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_024301.5(FKRP):​c.632C>T​(p.Ser211Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,403,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 7.21

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765
• PP5: Variant 19-46756082-C-T is Pathogenic according to our data. Variant chr19-46756082-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290094.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.632C>T	p.Ser211Leu	missense_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.632C>T	p.Ser211Leu	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000578 AC: 10 AN: 172996 Hom.: 0 AF XY: 0.0000409 AC XY: 4 AN XY: 97888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

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: 1403884 Hom.: 0 Cov.: 32 AF XY: 0.0000129 AC XY: 9 AN XY: 696038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000326

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000246

Gnomad4 FIN exome AF: 0.0000274

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000887 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

May 26, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Walker-Warburg congenital muscular dystrophy Pathogenic:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 211 of the FKRP protein (p.Ser211Leu). This variant is present in population databases (rs750041378, gnomAD 0.04%). This missense change has been observed in individuals with FKRP-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 290094). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FKRP protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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

Jul 09, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	L;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.051	T;T
Polyphen		1.0	D;D
Vest4		0.37
MutPred		0.49		Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);
MVP		0.95
MPC		1.5
ClinPred		0.61	D
GERP RS		4.3
Varity_R		0.60
gMVP		0.89

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: rs750041378; hg19: chr19-47259339;