2-47369516-C-G

Variant names:

• chr2-47369516-C-G
• rs778641299
• NM_002354.3:c.11C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002354.3(EPCAM):​c.11C>G​(p.Pro4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,411,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. P4L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EPCAM NM_002354.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.251
• Publications: 2 publications found

Genes affected

EPCAM (HGNC:11529): (epithelial cell adhesion molecule) This gene encodes a carcinoma-associated antigen and is a member of a family that includes at least two type I membrane proteins. This antigen is expressed on most normal epithelial cells and gastrointestinal carcinomas and functions as a homotypic calcium-independent cell adhesion molecule. The antigen is being used as a target for immunotherapy treatment of human carcinomas. Mutations in this gene result in congenital tufting enteropathy. [provided by RefSeq, Dec 2008]

EPCAM Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Lynch syndrome 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital diarrhea 5 with tufting enteropathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1611779).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002354.3. 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
	EPCAM	NM_002354.3	MANE Select	c.11C>G	p.Pro4Arg	missense	Exon 1 of 9	NP_002345.2	P16422

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	ENST00000263735.9	TSL:1 MANE Select	c.11C>G	p.Pro4Arg	missense	Exon 1 of 9	ENSP00000263735.4	P16422
	EPCAM	ENST00000895681.1		c.11C>G	p.Pro4Arg	missense	Exon 1 of 9	ENSP00000565740.1
	EPCAM	ENST00000895685.1		c.11C>G	p.Pro4Arg	missense	Exon 1 of 9	ENSP00000565744.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1411234 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698524

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31466

American (AMR) AF: 0.00 AC: 0 AN: 37434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25016

East Asian (EAS) AF: 0.00 AC: 0 AN: 37338

South Asian (SAS) AF: 0.00 AC: 0 AN: 79924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4230

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1092772

Other (OTH) AF: 0.00 AC: 0 AN: 58584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000854 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	11
DANN	Benign	0.65
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.25
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.23
Sift	Benign	0.69	T
Sift4G	Benign	0.087	T
Polyphen		0.94	P
Vest4		0.28
MutPred		0.27		Loss of loop (P = 0.0073)
MVP		0.36
MPC		0.013
ClinPred		0.21	T
GERP RS		1.2
PromoterAI		0.15	Neutral
Varity_R		0.042
gMVP		0.65
Mutation Taster		=86/14	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: rs778641299; hg19: chr2-47596655;