rs4540995

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_013382.7(POMT2):c.1654-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,614,048 control chromosomes in the GnomAD database, including 10,268 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1827 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8441 hom. )

Consequence

POMT2
NM_013382.7 splice_region, intron

Scores

Splicing: ADA: 0.0001492

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.567

Publications

17 publications found

Variant links:

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]

POMT2 Gene-Disease associations (from GenCC):

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
myopathy caused by variation in POMT2
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
autosomal recessive limb-girdle muscular dystrophy type 2N
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy with cerebellar involvement
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital muscular dystrophy with intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscle-eye-brain disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
muscular dystrophy-dystroglycanopathy, type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

POMT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 14-77280469-T-C is Benign according to our data. Variant chr14-77280469-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMT2	NM_013382.7 link	c.1654-6A>G		splice_region_variant, intron_variant	Intron 15 of 20	ENST00000261534.9	NP_037514.2	Q9UKY4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMT2	ENST00000261534.9 link	c.1654-6A>G		splice_region_variant, intron_variant	Intron 15 of 20	1	NM_013382.7	ENSP00000261534.4		Q9UKY4-1

Frequencies

GnomAD3 genomes

AF:

0.140

AC:

21260

AN:

152088

Hom.:

1821

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.0931

Gnomad ASJ

AF:

0.0910

Gnomad EAS

AF:

0.214

Gnomad SAS

AF:

0.0556

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.124

GnomAD2 exomes

AF:

0.109

AC:

27303

AN:

251418

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.241

Gnomad AMR exome

AF:

0.0614

Gnomad ASJ exome

AF:

0.0934

Gnomad EAS exome

AF:

0.225

Gnomad FIN exome

AF:

0.108

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.100

AC:

146541

AN:

1461842

Hom.:

8441

Cov.:

AF XY:

0.0984

AC XY:

71594

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.243

AC:

8120

AN:

33480

American (AMR)

AF:

0.0638

AC:

2854

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0974

AC:

2546

AN:

26134

East Asian (EAS)

AF:

0.230

AC:

9124

AN:

39700

South Asian (SAS)

AF:

0.0520

AC:

4486

AN:

86256

European-Finnish (FIN)

AF:

0.104

AC:

5577

AN:

53394

Middle Eastern (MID)

AF:

0.0978

AC:

564

AN:

5768

European-Non Finnish (NFE)

AF:

0.0962

AC:

106919

AN:

1111998

Other (OTH)

AF:

0.105

AC:

6351

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

9254

18508

27763

37017

46271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3956

7912

11868

15824

19780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.140

AC:

21288

AN:

152206

Hom.:

1827

Cov.:

AF XY:

0.138

AC XY:

10296

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.232

AC:

9626

AN:

41512

American (AMR)

AF:

0.0928

AC:

1419

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0910

AC:

316

AN:

3472

East Asian (EAS)

AF:

0.214

AC:

1108

AN:

5170

South Asian (SAS)

AF:

0.0559

AC:

270

AN:

4832

European-Finnish (FIN)

AF:

0.108

AC:

1145

AN:

10604

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7047

AN:

68010

Other (OTH)

AF:

0.123

AC:

261

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

926

1851

2777

3702

4628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.108

Hom.:

2147

Bravo

AF:

0.144

Asia WGS

AF:

0.110

AC:

385

AN:

3478

EpiCase

AF:

0.102

EpiControl

AF:

0.107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.1654-6A>G in intron 15 of POMT2: This variant is not expected to have clinical significance because it has been identified in 23% (1034/4406) of African Ameri can chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/; dbSNP rs4540995). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 18, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2N

Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

7.0

(source)

DANN

Benign

0.73

PhyloP100

0.57

PromoterAI

0.0014

Neutral

(source)

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.028

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over