Variant rs267606971 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_013382.7(POMT2):c.551C>T(p.Thr184Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,108 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: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

POMT2
NM_013382.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 9.63

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 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

PP5

Variant 14-77302940-G-A is Pathogenic according to our data. Variant chr14-77302940-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-77302940-G-A is described in Lovd as [Pathogenic]. Variant chr14-77302940-G-A is described in Lovd as [Pathogenic]. Variant chr14-77302940-G-A is described in Lovd as [Likely_pathogenic]. Variant chr14-77302940-G-A 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.551C>T	p.Thr184Met	missense_variant	5/21	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.551C>T	p.Thr184Met	missense_variant	5/21	1	NM_013382.7	ENSP00000261534.4		Q9UKY4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248200

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134142

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

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:

0.00000617

AC:

AN:

1458108

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725440

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000541

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000526

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2;C3150416:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2;C3150418:Autosomal recessive limb-girdle muscular dystrophy type 2N

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 184 of the POMT2 protein (p.Thr184Met). This variant is present in population databases (rs267606971, gnomAD 0.003%). This missense change has been observed in individuals with muscular dystrophy-dystroglycanopathy (PMID: 17878207, 17923109, 25214167, 27447704, 30060766, 32528171, 33176815, 34413876). ClinVar contains an entry for this variant (Variation ID: 3229). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POMT2 protein function with a negative predictive value of 95%. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 15, 2024	- -

Autosomal recessive limb-girdle muscular dystrophy type 2N

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 30, 2007	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 04, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 21, 2020	- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 13, 2024

Variant summary: POMT2 c.551C>T (p.Thr184Met) results in a non-conservative amino acid change located in the Glycosyl transferase family 39/83 domain (IPR003342) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248200 control chromosomes. c.551C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Biancheri_2007, Chen_2021, Godfrey_2007, Lin_2020, Panicucci_2023, Savarese_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17923109, 34413876, 17878207, 33176815, 36797079, 25214167). ClinVar contains an entry for this variant (Variation ID: 3229). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 25, 2024

- -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.5

L;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.6

N;N

REVEL

Pathogenic

0.83

Sift

Benign

0.048

D;T

Sift4G

Benign

0.083

T;T

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.74

Gain of catalytic residue at T184 (P = 0);.;

MVP

0.96

MPC

0.46

ClinPred

0.76

GERP RS

5.5

Varity_R

0.49

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

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