chr19-46756663-G-T

Variant names:

• chr19-46756663-G-T
• rs28937904
• NM_024301.5:c.1213G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_024301.5(FKRP):​c.1213G>T​(p.Val405Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.58

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a strand (size 7) in uniprot entity FKRP_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_024301.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 19-46756663-G-T is Pathogenic according to our data. Variant chr19-46756663-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4227.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-46756663-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.1213G>T	p.Val405Leu	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.1213G>T	p.Val405Leu	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4
FKRP	ENST00000391909.7	c.1213G>T	p.Val405Leu	missense_variant	Exon 4 of 4	2		ENSP00000375776.2
FKRP	ENST00000597339.5	n.247-5170G>T		intron_variant	Intron 3 of 3	5
FKRP	ENST00000600646.5	n.247+7998G>T		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy type B5 Pathogenic:1

Feb 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1

Jun 06, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.88
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;D
Vest4		0.71
MutPred		0.67		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.95
MPC		1.6
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28937904; hg19: chr19-47259920;