9-127935769-A-G

Variant names:

• chr9-127935769-A-G
• rs759597928
• NM_003863.4:c.208T>C

Variant summary

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

The NM_003863.4(DPM2):​c.208T>C​(p.Ser70Pro) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S70A) has been classified 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: 0.790
• 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=0.3912475).

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.208T>C	p.Ser70Pro	missense	Exon 4 of 4	NP_003854.1	O94777
	DPM2	NM_001378437.1		c.118T>C	p.Ser40Pro	missense	Exon 3 of 3	NP_001365366.1
	DPM2	NR_165631.1		n.365T>C		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.208T>C	p.Ser70Pro	missense	Exon 4 of 4	ENSP00000322181.8	O94777
	DPM2	ENST00000470181.1	TSL:1	n.500T>C		non_coding_transcript_exon	Exon 3 of 3
	DPM2	ENST00000495270.1	TSL:1	n.992T>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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	0.26
BayesDel_addAF	Benign	0.00070	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.65	T
PhyloP100		0.79
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.45
Sift	Benign	0.043	D
Sift4G	Benign	0.12	T
Polyphen		0.14	B
Vest4		0.22
MutPred		0.76		Loss of helix (P = 0.0068)
MVP		0.66
MPC		0.85
ClinPred		0.69	D
GERP RS		4.1
Varity_R		0.80
gMVP		0.85
Mutation Taster		=81/19	polymorphism

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: rs759597928; hg19: chr9-130698048;