chr14-77302940-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_013382.7(POMT2):c.551C>T(p.Thr184Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T184T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

POMT2
NM_013382.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 9.63

Publications

9 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: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_013382.7

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

PP5

Variant 14-77302940-G-A is Pathogenic according to our data. Variant chr14-77302940-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMT2	NM_013382.7 link	c.551C>T	p.Thr184Met	missense_variant	Exon 5 of 21	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.551C>T	p.Thr184Met	missense_variant	Exon 5 of 21	1	NM_013382.7	ENSP00000261534.4		Q9UKY4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248200

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000617

AC:

AN:

1458108

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33374

American (AMR)

AF:

0.0000224

AC:

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000541

AC:

AN:

1109186

Other (OTH)

AF:

0.0000166

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.0000145

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:2

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 184 of the POMT2 protein (p.Thr184Met). This variant is present in population databases (rs267606971, gnomAD 0.003%). This missense change has been observed in individuals with muscular dystrophy-dystroglycanopathy (PMID: 17878207, 17923109, 25214167, 27447704, 30060766, 32528171, 33176815, 34413876). ClinVar contains an entry for this variant (Variation ID: 3229). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POMT2 protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jun 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2N

Pathogenic:2

Nov 30, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 04, 2022

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Feb 21, 2020

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:2

Jan 25, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 27, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest a damaging effect of the variant on gene or gene product [REVEL: 0.83 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.36 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003229 /PMID: 17878207). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Jun 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: POMT2 c.551C>T (p.Thr184Met) results in a non-conservative amino acid change located in the Glycosyl transferase family 39/83 domain (IPR003342) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248200 control chromosomes. c.551C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Biancheri_2007, Chen_2021, Godfrey_2007, Lin_2020, Panicucci_2023, Savarese_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17923109, 34413876, 17878207, 33176815, 36797079, 25214167). ClinVar contains an entry for this variant (Variation ID: 3229). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.5

L;.

PhyloP100

9.6

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.6

N;N

REVEL

Pathogenic

0.83

Sift

Benign

0.048

D;T

Sift4G

Benign

0.083

T;T

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.74

Gain of catalytic residue at T184 (P = 0);.;

MVP

0.96

MPC

0.46

ClinPred

0.76

GERP RS

5.5

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.49

gMVP

0.68

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over