rs764015186

chr14-77299507-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM2 BP4_Strong BP6 BS1

The NM_013382.7(POMT2):c.871C>G(p.Leu291Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: POMT2 NM_013382.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.800

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity POMT2_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_013382.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0126821995).
• BP6: Variant 14-77299507-G-C is Benign according to our data. Variant chr14-77299507-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436382.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000526 (8/152196) while in subpopulation EAS AF= 0.00154 (8/5194). AF 95% confidence interval is 0.000766. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMT2	NM_013382.7	c.871C>G	p.Leu291Val	missense_variant	7/21	ENST00000261534.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT2	ENST00000261534.9	c.871C>G	p.Leu291Val	missense_variant	7/21	1	NM_013382.7	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 251444 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00294

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: 0.0000342 AC: 50 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000932

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000239 AC: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 11, 2015

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	14
Dann	Benign	0.94
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.22
Sift	Benign	0.77	T
Sift4G	Benign	0.85	T
Polyphen		0.019	B
Vest4		0.23
MutPred		0.62		Gain of catalytic residue at Y294 (P = 0);
MVP		0.62
MPC		0.094
ClinPred		0.026	T
GERP RS		1.1
Varity_R		0.042
gMVP		0.56

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: rs764015186; hg19: chr14-77765850;