rs146588608

chr14-77279833-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_013382.7(POMT2):c.1881G>A(p.Ala627=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,613,352 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (10 hom.)
• Consequence: POMT2 NM_013382.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.433

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 14-77279833-C-T is Benign according to our data. Variant chr14-77279833-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194863.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4, Likely_benign=1}. Variant chr14-77279833-C-T is described in Lovd as [Likely_benign]. Variant chr14-77279833-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.433 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00171 (260/152218) while in subpopulation SAS AF= 0.00539 (26/4826). AF 95% confidence interval is 0.00378. There are 1 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMT2	NM_013382.7	c.1881G>A	p.Ala627=	synonymous_variant	18/21	ENST00000261534.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT2	ENST00000261534.9	c.1881G>A	p.Ala627=	synonymous_variant	18/21	1	NM_013382.7	P1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152100 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00207 AC: 515 AN: 249220 Hom.: 1 AF XY: 0.00235 AC XY: 317 AN XY: 134928

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.00662

Gnomad FIN exome AF: 0.000282

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00275 AC: 4020 AN: 1461134 Hom.: 10 Cov.: 33 AF XY: 0.00291 AC XY: 2116 AN XY: 726830

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00647

Gnomad4 FIN exome AF: 0.000679

Gnomad4 NFE exome AF: 0.00289

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152218 Hom.: 1 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74424

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00182 Hom.: 0

Bravo AF: 0.00148

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	POMT2: BP4, BP7 -

Autosomal recessive limb-girdle muscular dystrophy type 2N Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	1.8
Dann	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs146588608; hg19: chr14-77746176;