NM_003863.4:c.227C>G

Variant names:

• chr9-127935750-G-C
• rs7997
• NM_003863.4:c.227C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T76A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.79 (48010 hom., cov: 32)
  • Exomes 𝑓: 0.84 (519404 hom.)
• Consequence: DPM2 NM_003863.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0340
• Publications: 41 publications found

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 Gene-Disease associations (from GenCC):

• congenital muscular dystrophy with intellectual disability and severe epilepsy

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet

ENSG00000227218 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DPM2	NM_003863.4	c.227C>G	p.Thr76Ser	missense_variant	Exon 4 of 4	ENST00000314392.13	NP_003854.1
DPM2	NM_001378437.1	c.137C>G	p.Thr46Ser	missense_variant	Exon 3 of 3		NP_001365366.1
DPM2	NR_165631.1	n.384C>G		non_coding_transcript_exon_variant	Exon 4 of 4
DPM2	NR_165632.1	n.68C>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPM2	ENST00000314392.13	c.227C>G	p.Thr76Ser	missense_variant	Exon 4 of 4	1	NM_003863.4	ENSP00000322181.8

Frequencies

GnomAD3 genomes AF: 0.787 AC: 119613 AN: 151924 Hom.: 47973 Cov.: 32

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

GnomAD2 exomes AF: 0.789 AC: 197919 AN: 250700 AF XY: 0.791

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 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.: 51 AF XY: 0.835 AC XY: 606011 AN XY: 725692

African (AFR) AF: 0.675 AC: 22521 AN: 33362

American (AMR) AF: 0.815 AC: 36398 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 18933 AN: 26084

East Asian (EAS) AF: 0.421 AC: 16703 AN: 39674

South Asian (SAS) AF: 0.705 AC: 60723 AN: 86114

European-Finnish (FIN) AF: 0.867 AC: 46284 AN: 53354

Middle Eastern (MID) AF: 0.741 AC: 4275 AN: 5766

European-Non Finnish (NFE) AF: 0.873 AC: 968852 AN: 1109334

Other (OTH) AF: 0.809 AC: 48772 AN: 60264

GnomAD4 genome AF: 0.787 AC: 119698 AN: 152044 Hom.: 48010 Cov.: 32 AF XY: 0.783 AC XY: 58165 AN XY: 74312

African (AFR) AF: 0.672 AC: 27851 AN: 41432

American (AMR) AF: 0.819 AC: 12509 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.728 AC: 2525 AN: 3470

East Asian (EAS) AF: 0.455 AC: 2341 AN: 5148

South Asian (SAS) AF: 0.675 AC: 3257 AN: 4824

European-Finnish (FIN) AF: 0.869 AC: 9216 AN: 10602

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.872 AC: 59286 AN: 67972

Other (OTH) AF: 0.785 AC: 1656 AN: 2110

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

Submissions by phenotype

Congenital muscular dystrophy with intellectual disability and severe epilepsy Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.86
DANN	Benign	0.75
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.034
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.051
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.16		Loss of relative solvent accessibility (P = 0.0306);
MPC		0.55
ClinPred		0.0023	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7997; hg19: chr9-130698029; COSMIC: COSV58709021; COSMIC: COSV58709021;