rs7997

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-127935750-G-C
• chr9-127935750-G-T

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: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003863.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPM2	NM_003863.4	MANE Select	c.227C>G	p.Thr76Ser	missense	Exon 4 of 4	NP_003854.1	O94777
	DPM2	NM_001378437.1		c.137C>G	p.Thr46Ser	missense	Exon 3 of 3	NP_001365366.1
	DPM2	NR_165631.1		n.384C>G		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPM2	ENST00000314392.13	TSL:1 MANE Select	c.227C>G	p.Thr76Ser	missense	Exon 4 of 4	ENSP00000322181.8	O94777
	DPM2	ENST00000470181.1	TSL:1	n.519C>G		non_coding_transcript_exon	Exon 3 of 3
	DPM2	ENST00000495270.1	TSL:1	n.1011C>G		non_coding_transcript_exon	Exon 3 of 3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Congenital muscular dystrophy with intellectual disability and severe epilepsy (4)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;