9-127935750-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003863.4(DPM2):​c.227C>A​(p.Thr76Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T76S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPM2 NM_003863.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060724854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPM2	NM_003863.4	c.227C>A	p.Thr76Asn	missense_variant	Exon 4 of 4	ENST00000314392.13	NP_003854.1
DPM2	NM_001378437.1	c.137C>A	p.Thr46Asn	missense_variant	Exon 3 of 3		NP_001365366.1
DPM2	NR_165631.1	n.384C>A		non_coding_transcript_exon_variant	Exon 4 of 4
DPM2	NR_165632.1	n.68C>A		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>A	p.Thr76Asn	missense_variant	Exon 4 of 4	1	NM_003863.4	ENSP00000322181.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 37159

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.2
DANN	Benign	0.74
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.034
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.043
Sift	Benign	0.43	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.065
MutPred		0.38		Loss of phosphorylation at T76 (P = 0.0477);
MVP		0.45
MPC		0.70
ClinPred		0.047	T
GERP RS		2.7
Varity_R		0.031
gMVP		0.50
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;