2-47373967-T-C

Variant names:

• chr2-47373967-T-C
• rs1126497
• NM_002354.3:c.344T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002354.3(EPCAM):​c.344T>C​(p.Met115Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,613,628 control chromosomes in the GnomAD database, including 193,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M115R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.58 (27738 hom., cov: 31)
  • Exomes 𝑓: 0.47 (166258 hom.)
• Consequence: EPCAM NM_002354.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0500
• Publications: 77 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.3098158E-6).
• BP6: Variant 2-47373967-T-C is Benign according to our data. Variant chr2-47373967-T-C is described in ClinVar as Benign. ClinVar VariationId is 183700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

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.344T>C	p.Met115Thr	missense	Exon 3 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.344T>C	p.Met115Thr	missense	Exon 3 of 9	ENSP00000263735.4	P16422
	EPCAM	ENST00000405271.5	TSL:5	c.428T>C	p.Met143Thr	missense	Exon 4 of 10	ENSP00000385476.1	B5MCA4
	EPCAM	ENST00000895681.1		c.344T>C	p.Met115Thr	missense	Exon 3 of 9	ENSP00000565740.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87547 AN: 151766 Hom.: 27689 Cov.: 31

Gnomad AFR AF: 0.831

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.526

GnomAD2 exomes AF: 0.513 AC: 129014 AN: 251424 AF XY: 0.501

Gnomad AFR exome AF: 0.842

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.832

Gnomad FIN exome AF: 0.596

Gnomad NFE exome AF: 0.436

Gnomad OTH exome AF: 0.464

GnomAD4 exome AF: 0.467 AC: 683281 AN: 1461744 Hom.: 166258 Cov.: 45 AF XY: 0.466 AC XY: 338676 AN XY: 727182

African (AFR) AF: 0.849 AC: 28436 AN: 33480

American (AMR) AF: 0.474 AC: 21210 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 9609 AN: 26134

East Asian (EAS) AF: 0.790 AC: 31354 AN: 39700

South Asian (SAS) AF: 0.480 AC: 41378 AN: 86258

European-Finnish (FIN) AF: 0.592 AC: 31632 AN: 53414

Middle Eastern (MID) AF: 0.383 AC: 2208 AN: 5768

European-Non Finnish (NFE) AF: 0.438 AC: 487525 AN: 1111880

Other (OTH) AF: 0.496 AC: 29929 AN: 60392

GnomAD4 genome AF: 0.577 AC: 87649 AN: 151884 Hom.: 27738 Cov.: 31 AF XY: 0.582 AC XY: 43171 AN XY: 74194

African (AFR) AF: 0.831 AC: 34451 AN: 41454

American (AMR) AF: 0.494 AC: 7513 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1262 AN: 3472

East Asian (EAS) AF: 0.816 AC: 4214 AN: 5164

South Asian (SAS) AF: 0.498 AC: 2400 AN: 4820

European-Finnish (FIN) AF: 0.591 AC: 6210 AN: 10504

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30066 AN: 67946

Other (OTH) AF: 0.525 AC: 1105 AN: 2106

Alfa AF: 0.480 Hom.: 63144

Bravo AF: 0.580

TwinsUK AF: 0.446 AC: 1654

ALSPAC AF: 0.435 AC: 1676

ESP6500AA AF: 0.828 AC: 3649

ESP6500EA AF: 0.433 AC: 3722

ExAC AF: 0.520 AC: 63080

Asia WGS AF: 0.658 AC: 2287 AN: 3478

EpiCase AF: 0.422

EpiControl AF: 0.412

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Congenital diarrhea 5 with tufting enteropathy (1)
-	-	1	Lynch syndrome 1 (1)
-	-	1	Lynch syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.74
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.018	T
MetaRNN	Benign	0.0000033	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.050
PrimateAI	Benign	0.31	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.013
ClinPred		0.0024	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.36
Mutation Taster		=97/3	polymorphism (auto)

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: rs1126497; hg19: chr2-47601106; COSMIC: COSV55392922; COSMIC: COSV55392922;