rs7997

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003863.4(DPM2):c.227C>G(p.Thr76Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 1,610,654 control chromosomes in the GnomAD database, including 567,414 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.79 ( 48010 hom., cov: 32)

Exomes 𝑓: 0.84 ( 519404 hom. )

Consequence

DPM2
NM_003863.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0340

Variant links:

Genes affected

DPM2 (HGNC:3006): (dolichyl-phosphate mannosyltransferase subunit 2, regulatory) Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. The protein encoded by this gene is a hydrophobic protein that contains 2 predicted transmembrane domains and a putative ER localization signal near the C terminus. This protein associates with DPM1 in vivo and is required for the ER localization and stable expression of DPM1 and also enhances the binding of dolichol-phosphate to DPM1. [provided by RefSeq, Jul 2008]

DPM2 links:

DPM2 (HGNC:):

DPM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.1462935E-7).

BP6

Variant 9-127935750-G-C is Benign according to our data. Variant chr9-127935750-G-C is described in ClinVar as [Benign]. Clinvar id is 128921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127935750-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPM2	NM_003863.4 linkuse as main transcript	c.227C>G	p.Thr76Ser	missense_variant	4/4	ENST00000314392.13	NP_003854.1	O94777
DPM2	NM_001378437.1 linkuse as main transcript	c.137C>G	p.Thr46Ser	missense_variant	3/3		NP_001365366.1
DPM2	NR_165631.1 linkuse as main transcript	n.384C>G		non_coding_transcript_exon_variant	4/4
DPM2	NR_165632.1 linkuse as main transcript	n.68C>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPM2	ENST00000314392.13 linkuse as main transcript	c.227C>G	p.Thr76Ser	missense_variant	4/4	1	NM_003863.4	ENSP00000322181.8		O94777

Frequencies

GnomAD3 genomes

AF:

0.787

AC:

119613

AN:

151924

Hom.:

47973

Cov.:

show subpopulations

Gnomad AFR

AF:

0.672

Gnomad AMI

AF:

0.919

Gnomad AMR

AF:

0.819

Gnomad ASJ

AF:

0.728

Gnomad EAS

AF:

0.455

Gnomad SAS

AF:

0.674

Gnomad FIN

AF:

0.869

Gnomad MID

AF:

0.752

Gnomad NFE

AF:

0.872

Gnomad OTH

AF:

0.783

GnomAD3 exomes

AF:

0.789

AC:

197919

AN:

250700

Hom.:

79920

AF XY:

0.791

AC XY:

107164

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.667

Gnomad AMR exome

AF:

0.813

Gnomad ASJ exome

AF:

0.731

Gnomad EAS exome

AF:

0.459

Gnomad SAS exome

AF:

0.704

Gnomad FIN exome

AF:

0.864

Gnomad NFE exome

AF:

0.867

Gnomad OTH exome

AF:

0.800

GnomAD4 exome

AF:

0.839

AC:

1223461

AN:

1458610

Hom.:

519404

Cov.:

AF XY:

0.835

AC XY:

606011

AN XY:

725692

show subpopulations

Gnomad4 AFR exome

AF:

0.675

Gnomad4 AMR exome

AF:

0.815

Gnomad4 ASJ exome

AF:

0.726

Gnomad4 EAS exome

AF:

0.421

Gnomad4 SAS exome

AF:

0.705

Gnomad4 FIN exome

AF:

0.867

Gnomad4 NFE exome

AF:

0.873

Gnomad4 OTH exome

AF:

0.809

GnomAD4 genome

AF:

0.787

AC:

119698

AN:

152044

Hom.:

48010

Cov.:

AF XY:

0.783

AC XY:

58165

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.672

Gnomad4 AMR

AF:

0.819

Gnomad4 ASJ

AF:

0.728

Gnomad4 EAS

AF:

0.455

Gnomad4 SAS

AF:

0.675

Gnomad4 FIN

AF:

0.869

Gnomad4 NFE

AF:

0.872

Gnomad4 OTH

AF:

0.785

Alfa

AF:

0.835

Hom.:

37159

Bravo

AF:

0.778

TwinsUK

AF:

0.865

AC:

3209

ALSPAC

AF:

0.861

AC:

3317

ESP6500AA

AF:

0.680

AC:

2996

ESP6500EA

AF:

0.868

AC:

7466

ExAC

AF:

0.787

AC:

95556

Asia WGS

AF:

0.617

AC:

2148

AN:

3478

EpiCase

AF:

0.855

EpiControl

AF:

0.856

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital muscular dystrophy with intellectual disability and severe epilepsy

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.86

DANN

Benign

0.75

DEOGEN2

Benign

0.11

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.26

MetaRNN

Benign

8.1e-7

MetaSVM

Benign

-0.94

PrimateAI

Benign

0.40

PROVEAN

Benign

1.8

REVEL

Benign

0.051

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.028

MutPred

0.16

Loss of relative solvent accessibility (P = 0.0306);

MPC

0.55

ClinPred

0.0023

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over