NM_002354.3:c.267G>C

Variant names:

• chr2-47373890-G-C
• rs146480420
• NM_002354.3:c.267G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002354.3(EPCAM):​c.267G>C​(p.Gln89His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,614,118 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q89R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (22 hom.)
• Consequence: EPCAM NM_002354.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.971
• Publications: 17 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), PanelApp Australia, Orphanet, G2P, Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013347268).
• BP6: Variant 2-47373890-G-C is Benign according to our data. Variant chr2-47373890-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127848.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00284 (433/152236) while in subpopulation NFE AF = 0.00503 (342/68018). AF 95% confidence interval is 0.00459. There are 3 homozygotes in GnomAd4. There are 191 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	NM_002354.3	MANE Select	c.267G>C	p.Gln89His	missense	Exon 3 of 9	NP_002345.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	ENST00000263735.9	TSL:1 MANE Select	c.267G>C	p.Gln89His	missense	Exon 3 of 9	ENSP00000263735.4
	EPCAM	ENST00000405271.5	TSL:5	c.351G>C	p.Gln117His	missense	Exon 4 of 10	ENSP00000385476.1
	EPCAM	ENST00000895681.1		c.267G>C	p.Gln89His	missense	Exon 3 of 9	ENSP00000565740.1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 433 AN: 152118 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00503

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00272 AC: 684 AN: 251466 AF XY: 0.00284

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00452 AC: 6604 AN: 1461882 Hom.: 22 Cov.: 33 AF XY: 0.00440 AC XY: 3198 AN XY: 727246

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00215 AC: 96 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86256

European-Finnish (FIN) AF: 0.00118 AC: 63 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00555 AC: 6174 AN: 1112002

Other (OTH) AF: 0.00308 AC: 186 AN: 60396

GnomAD4 genome AF: 0.00284 AC: 433 AN: 152236 Hom.: 3 Cov.: 32 AF XY: 0.00257 AC XY: 191 AN XY: 74418

African (AFR) AF: 0.00130 AC: 54 AN: 41548

American (AMR) AF: 0.00138 AC: 21 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00503 AC: 342 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00403 Hom.: 3

Bravo AF: 0.00292

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00258 AC: 313

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00462

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not specified (2)
-	-	1	EPCAM-related disorder (1)
-	-	1	Lynch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.97
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.49		Gain of helix (P = 0.0164)
MVP		0.66
MPC		0.078
ClinPred		0.036	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.53
Mutation Taster		=67/33	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: rs146480420; hg19: chr2-47601029; COSMIC: COSV104560651;