rs267606964

chr14-77277387-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_013382.7(POMT2):c.2242T>C(p.Trp748Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W748S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POMT2 NM_013382.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-77277386-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 3230.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 14-77277387-A-G is Pathogenic according to our data. Variant chr14-77277387-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3224.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-77277387-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMT2	NM_013382.7	c.2242T>C	p.Trp748Arg	missense_variant	21/21	ENST00000261534.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT2	ENST00000261534.9	c.2242T>C	p.Trp748Arg	missense_variant	21/21	1	NM_013382.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2022

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. This variant disrupts the p.Trp748 amino acid residue in POMT2. Other variant(s) that disrupt this residue have been observed in individuals with POMT2-related conditions (PMID: 17878207), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects POMT2 function (PMID: 17869517). 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 expected to disrupt POMT2 protein function. ClinVar contains an entry for this variant (Variation ID: 3224). This missense change has been observed in individual(s) with POMT2-related conditions (PMID: 17634419). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 748 of the POMT2 protein (p.Trp748Arg). -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 18, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.86		Gain of disorder (P = 0.0054);
MVP		0.98
MPC		0.61
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.94

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: rs267606964; hg19: chr14-77743730;