rs142299878

Positions:

• chr14-77278858-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000261534.9(POMT2):​c.1903G>A​(p.Val635Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00098 in 1,613,240 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: POMT2 ENST00000261534.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 2.48

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031135172).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000624 (95/152310) while in subpopulation NFE AF= 0.0011 (75/68024). AF 95% confidence interval is 0.000902. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMT2	NM_013382.7	c.1903G>A	p.Val635Ile	missense_variant	19/21	ENST00000261534.9	NP_037514.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMT2	ENST00000261534.9	c.1903G>A	p.Val635Ile	missense_variant	19/21	1	NM_013382.7	ENSP00000261534	P1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000492 AC: 123 AN: 249938 Hom.: 0 AF XY: 0.000532 AC XY: 72 AN XY: 135356

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.000914

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.00102 AC: 1486 AN: 1460930 Hom.: 2 Cov.: 34 AF XY: 0.00101 AC XY: 734 AN XY: 726800

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000947

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74478

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000789 Hom.: 0

Bravo AF: 0.000778

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.00153

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 13, 2023	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2019	Reported in a fetus with lissencephaly without an identified second POMT2 variant (Bouchet et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17559086, 30564623) -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 31, 2021	- -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 635 of the POMT2 protein (p.Val635Ile). This variant is present in population databases (rs142299878, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with type II lissencephaly (PMID: 17559086). ClinVar contains an entry for this variant (Variation ID: 194965). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.71	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.15
Sift	Benign	0.21	T
Sift4G	Benign	0.18	T
Polyphen		0.018	B
Vest4		0.16
MVP		0.50
MPC		0.068
ClinPred		0.013	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.46

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: rs142299878; hg19: chr14-77745201;