11-119107855-G-C

Variant names:

• chr11-119107855-G-C
• rs1477205603
• NM_001290474.2:c.114G>C

Variant summary

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

The NM_001290474.2(C2CD2L):​c.114G>C​(p.Trp38Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000218 in 1,374,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. W38G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: C2CD2L NM_001290474.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90
• 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.114G>C	p.Trp38Cys	missense	Exon 1 of 14	NP_001277403.1	O14523-1
	C2CD2L	NM_014807.5		c.114G>C	p.Trp38Cys	missense	Exon 1 of 14	NP_055622.3
	C2CD2L	NM_001382613.1		c.114G>C	p.Trp38Cys	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.114G>C	p.Trp38Cys	missense	Exon 1 of 14	ENSP00000497391.1	O14523-1
	C2CD2L	ENST00000336702.7	TSL:1	c.114G>C	p.Trp38Cys	missense	Exon 1 of 14	ENSP00000338885.3	O14523-2
	C2CD2L	ENST00000861321.1		c.114G>C	p.Trp38Cys	missense	Exon 1 of 14	ENSP00000531380.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000160 AC: 2 AN: 125286 AF XY: 0.0000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000926

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: 0.00000218 AC: 3 AN: 1374994 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 681152

African (AFR) AF: 0.00 AC: 0 AN: 28060

American (AMR) AF: 0.0000595 AC: 2 AN: 33630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24210

East Asian (EAS) AF: 0.00 AC: 0 AN: 32126

South Asian (SAS) AF: 0.00 AC: 0 AN: 77474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4326

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080034

Other (OTH) AF: 0.00 AC: 0 AN: 56996

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Benign	0.33
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.57		Loss of MoRF binding (P = 0.0083)
MVP		0.043
MPC		0.84
ClinPred		0.71	D
GERP RS		4.7
PromoterAI		-0.045	Neutral
Varity_R		0.42
gMVP		0.79
Mutation Taster		=77/23	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: rs1477205603; hg19: chr11-118978565;