NM_001290474.2:c.256C>T

Variant names:

• chr11-119107997-C-T
• rs980950180
• NM_001290474.2:c.256C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001290474.2(C2CD2L):​c.256C>T​(p.Arg86Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000253 in 1,583,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: C2CD2L NM_001290474.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03
• Publications: 0 publications found

Genes affected

C2CD2L (HGNC:29000): (C2CD2 like) Enables phosphatidylinositol binding activity and phosphatidylinositol transfer activity. Involved in positive regulation of insulin secretion involved in cellular response to glucose stimulus. Located in cortical endoplasmic reticulum and endoplasmic reticulum-plasma membrane contact site. Colocalizes with cytoplasmic side of apical plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

DPAGT1 (HGNC:2995): (dolichyl-phosphate N-acetylglucosaminephosphotransferase 1) The protein encoded by this gene is an enzyme that catalyzes the first step in the dolichol-linked oligosaccharide pathway for glycoprotein biosynthesis. This enzyme belongs to the glycosyltransferase family 4. This protein is an integral membrane protein of the endoplasmic reticulum. The congenital disorder of glycosylation type Ij is caused by mutation in the gene encoding this enzyme. [provided by RefSeq, Jul 2008]

DPAGT1 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• DPAGT1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290474.2. 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
	C2CD2L	NM_001290474.2	MANE Select	c.256C>T	p.Arg86Trp	missense	Exon 1 of 14	NP_001277403.1	O14523-1
	C2CD2L	NM_014807.5		c.256C>T	p.Arg86Trp	missense	Exon 1 of 14	NP_055622.3
	C2CD2L	NM_001382613.1		c.256C>T	p.Arg86Trp	missense	Exon 2 of 15	NP_001369542.1	O14523-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD2L	ENST00000648610.2	MANE Select	c.256C>T	p.Arg86Trp	missense	Exon 1 of 14	ENSP00000497391.1	O14523-1
	C2CD2L	ENST00000336702.7	TSL:1	c.256C>T	p.Arg86Trp	missense	Exon 1 of 14	ENSP00000338885.3	O14523-2
	C2CD2L	ENST00000861321.1		c.256C>T	p.Arg86Trp	missense	Exon 1 of 14	ENSP00000531380.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151904 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 201914 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1431120 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 712482

African (AFR) AF: 0.00 AC: 0 AN: 29640

American (AMR) AF: 0.0000248 AC: 1 AN: 40320

Ashkenazi Jewish (ASJ) AF: 0.0000404 AC: 1 AN: 24780

East Asian (EAS) AF: 0.00 AC: 0 AN: 35776

South Asian (SAS) AF: 0.00 AC: 0 AN: 84452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5526

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100258

Other (OTH) AF: 0.0000170 AC: 1 AN: 58912

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151904 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67888

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.35		Loss of disorder (P = 0.0205)
MVP		0.068
MPC		1.4
ClinPred		0.98	D
GERP RS		3.7
PromoterAI		0.056	Neutral
Varity_R		0.34
gMVP		0.58
Mutation Taster		=71/29	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: rs980950180; hg19: chr11-118978707;