9-127935748-T-C

Variant names:

• chr9-127935748-T-C
• rs1831494309
• NM_003863.4:c.229A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003863.4(DPM2):​c.229A>G​(p.Lys77Glu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPM2 NM_003863.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.714
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3341748).

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.229A>G	p.Lys77Glu	missense	Exon 4 of 4	NP_003854.1	O94777
	DPM2	NM_001378437.1		c.139A>G	p.Lys47Glu	missense	Exon 3 of 3	NP_001365366.1
	DPM2	NR_165631.1		n.386A>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.229A>G	p.Lys77Glu	missense	Exon 4 of 4	ENSP00000322181.8	O94777
	DPM2	ENST00000470181.1	TSL:1	n.521A>G		non_coding_transcript_exon	Exon 3 of 3
	DPM2	ENST00000495270.1	TSL:1	n.1013A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital muscular dystrophy with intellectual disability and severe epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.68
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.71
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.091
Sift	Benign	0.40	T
Sift4G	Benign	0.14	T
Polyphen		0.0070	B
Vest4		0.034
MutPred		0.56		Loss of MoRF binding (P = 8e-04)
MVP		0.38
MPC		0.86
ClinPred		0.032	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.28
Mutation Taster		=98/2	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: rs1831494309; hg19: chr9-130698027;