rs144748043

chr14-77302842-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_013382.7(POMT2):c.649G>A(p.Ala217Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,611,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A217A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: POMT2 NM_013382.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.02

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004279852).
• BP6: Variant 14-77302842-C-T is Benign according to our data. Variant chr14-77302842-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282839.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000631 (96/152242) while in subpopulation AFR AF= 0.00205 (85/41538). AF 95% confidence interval is 0.00169. There are 0 homozygotes in gnomad4. There are 44 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.649G>A	p.Ala217Thr	missense_variant	5/21	ENST00000261534.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMT2	ENST00000261534.9	c.649G>A	p.Ala217Thr	missense_variant	5/21	1	NM_013382.7	P1

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 250816 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135594

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 0.0000631 AC: 92 AN: 1458928 Hom.: 0 Cov.: 31 AF XY: 0.0000606 AC XY: 44 AN XY: 725954

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74420

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000140 Hom.: 0

Bravo AF: 0.000684

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000321 AC: 39

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	13
Dann	Benign	0.95
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.47	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.18
Sift	Benign	0.58	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.0010	B;.
Vest4		0.18
MVP		0.72
MPC		0.080
ClinPred		0.014	T
GERP RS		3.7
Varity_R		0.054
gMVP		0.23

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: rs144748043; hg19: chr14-77769185; COSMIC: COSV99836090; COSMIC: COSV99836090;