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

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPM2	NM_003863.4	c.208T>C	p.Ser70Pro	missense_variant	Exon 4 of 4	ENST00000314392.13	NP_003854.1
DPM2	NM_001378437.1	c.118T>C	p.Ser40Pro	missense_variant	Exon 3 of 3		NP_001365366.1
DPM2	NR_165631.1	n.365T>C		non_coding_transcript_exon_variant	Exon 4 of 4
DPM2	NR_165632.1	n.49T>C		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.208T>C	p.Ser70Pro	missense_variant	Exon 4 of 4	1	NM_003863.4	ENSP00000322181.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital muscular dystrophy with intellectual disability and severe epilepsy Uncertain:1

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1500243). This variant has not been reported in the literature in individuals affected with DPM2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 70 of the DPM2 protein (p.Ser70Pro). -

Computational scores

Source: dbNSFP v4.3

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;