9-127937459-T-G

Variant names:

• chr9-127937459-T-G
• rs397514503
• NM_003863.4:c.68A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_003863.4(DPM2):​c.68A>C​(p.Tyr23Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. Y23C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DPM2 NM_003863.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.70
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127937459-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 39446.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPM2	NM_003863.4	c.68A>C	p.Tyr23Ser	missense_variant	Exon 2 of 4	ENST00000314392.13	NP_003854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPM2	ENST00000314392.13	c.68A>C	p.Tyr23Ser	missense_variant	Exon 2 of 4	1	NM_003863.4	ENSP00000322181.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.31	D
PhyloP100		5.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.7	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.83		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.91
MPC		1.9
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.88
Mutation Taster		=16/84	disease causing

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: rs397514503; hg19: chr9-130699738;