Variant chr14-77296223-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_013382.7(POMT2):c.1057G>A(p.Gly353Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,457,072 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

POMT2
NM_013382.7 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.82

Variant links:

Genes affected

POMT2 (HGNC:19743): (protein O-mannosyltransferase 2) The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT1 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS).[provided by RefSeq, Oct 2008]

POMT2 links:

POMT2 (HGNC:):

POMT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain MIR 1 (size 56) in uniprot entity POMT2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_013382.7

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

PP5

Variant 14-77296223-C-T is Pathogenic according to our data. Variant chr14-77296223-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-77296223-C-T is described in Lovd as [Pathogenic]. Variant chr14-77296223-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMT2	NM_013382.7 linkuse as main transcript	c.1057G>A	p.Gly353Ser	missense_variant	9/21	ENST00000261534.9	NP_037514.2	Q9UKY4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMT2	ENST00000261534.9 linkuse as main transcript	c.1057G>A	p.Gly353Ser	missense_variant	9/21	1	NM_013382.7	ENSP00000261534.4		Q9UKY4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000125

AC:

AN:

240782

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

129684

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000346

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1457072

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

724124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000354

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 08, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 26, 2009

- -

POMT2-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2022

The POMT2 c.1057G>A variant is predicted to result in the amino acid substitution p.Gly353Ser. This variant was reported as causative in the compound heterozygous state in two patients with congenital muscular dystrophy with brain and eye anomalies (Mercuri et al. 2006. PubMed ID: 16701995; Godfrey et al. 2007. PubMed ID:17878207; Messina et al. 2008. PubMed ID: 18513969). This variant was observed in the homozygous or heterozygous states along with another pathogenic variant in three patients undergoing congenital muscular dystrophy testing at PreventionGenetics. This variant is reported in 0.0035% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-77762566-C-T). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19299310, 17878207, 11053679, 18513969, 16701995, 31589614, 32494558, 31069529, 35595449) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.90

Sift

Uncertain

0.013

Sift4G

Benign

0.075

Polyphen

1.0

Vest4

0.96

MutPred

0.81

Gain of catalytic residue at Y354 (P = 0.0044);

MVP

0.94

MPC

0.43

ClinPred

0.97

GERP RS

5.0

Varity_R

0.64

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over