rs138266415

Positions:

• chr14-77285568-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013382.7(POMT2):​c.1397G>A​(p.Arg466Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: POMT2 NM_013382.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.13

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07652369).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMT2	NM_013382.7	c.1397G>A	p.Arg466Gln	missense_variant	13/21	ENST00000261534.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT2	ENST00000261534.9	c.1397G>A	p.Arg466Gln	missense_variant	13/21	1	NM_013382.7	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000636 AC: 16 AN: 251490 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135920

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727160

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74290

Gnomad4 AFR AF: 0.000507

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Invitae

Sep 16, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 466 of the POMT2 protein (p.Arg466Gln). This variant is present in population databases (rs138266415, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with POMT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 471387). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.0028
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.077	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.55	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.26
Sift	Benign	0.61	T
Sift4G	Benign	0.60	T
Polyphen		0.16	B
Vest4		0.15
MVP		0.84
MPC		0.12
ClinPred		0.032	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.055
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138266415; hg19: chr14-77751911;