rs116429842

chr2-47369555-C-Achr2-47369555-C-Gchr2-47369555-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002354.3(EPCAM):c.50C>A(p.Thr17Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,588,506 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T17M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0098 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (31 hom.)
• Consequence: EPCAM NM_002354.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.913

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032449365).
• BP6: Variant 2-47369555-C-A is Benign according to our data. Variant chr2-47369555-C-A is described in ClinVar as [Benign]. Clinvar id is 137216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00975 (1485/152232) while in subpopulation AFR AF= 0.0321 (1332/41558). AF 95% confidence interval is 0.0306. There are 29 homozygotes in gnomad4. There are 682 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPCAM	NM_002354.3	c.50C>A	p.Thr17Lys	missense_variant	1/9	ENST00000263735.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPCAM	ENST00000263735.9	c.50C>A	p.Thr17Lys	missense_variant	1/9	1	NM_002354.3	P1

Frequencies

GnomAD3 genomes AF: 0.00974 AC: 1482 AN: 152118 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00214 AC: 434 AN: 202956 Hom.: 5 AF XY: 0.00164 AC XY: 182 AN XY: 110944

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.000338

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000114

Gnomad FIN exome AF: 0.0000580

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00127 AC: 1827 AN: 1436274 Hom.: 31 Cov.: 31 AF XY: 0.00113 AC XY: 803 AN XY: 712490

Gnomad4 AFR exome AF: 0.0353

Gnomad4 AMR exome AF: 0.00283

Gnomad4 ASJ exome AF: 0.000393

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000110

Gnomad4 FIN exome AF: 0.0000200

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00975 AC: 1485 AN: 152232 Hom.: 29 Cov.: 32 AF XY: 0.00916 AC XY: 682 AN XY: 74430

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00581

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00108 Hom.: 2

Bravo AF: 0.0116

ESP6500AA AF: 0.0296 AC: 127

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00244 AC: 292

Asia WGS AF: 0.00318 AC: 11 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Lynch syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 10, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2013

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	18
Dann	Benign	0.69
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.13
Sift	Benign	0.18	T;D
Sift4G	Benign	0.39	T;D
Polyphen		0.50	P;.
Vest4		0.46
MVP		0.44
MPC		0.093
ClinPred		0.025	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.075
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs116429842; hg19: chr2-47596694;