2-47373890-G-C

Variant summary

Our verdict is Benign. Variant got -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q89Q) has been classified as Likely benign.

• 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

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 -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 id is 127848.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=3, Uncertain_significance=1}. Variant chr2-47373890-G-C is described in Lovd as [Likely_benign]. Variant chr2-47373890-G-C is described in Lovd as [Pathogenic].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPCAM	NM_002354.3	c.267G>C	p.Gln89His	missense_variant	3/9	ENST00000263735.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPCAM	ENST00000263735.9	c.267G>C	p.Gln89His	missense_variant	3/9	1	NM_002354.3	P1

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

GnomAD3 exomes AF: 0.00272 AC: 684 AN: 251466 Hom.: 3 AF XY: 0.00284 AC XY: 386 AN XY: 135910

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 SAS exome AF: 0.000261

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

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.00555

Gnomad4 OTH exome AF: 0.00308

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

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00503

Gnomad4 OTH AF: 0.00142

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:7

Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2016	Variant summary: The EPCAM c.267G>C (p.Gln89His) variant causes a missense change involving a non-conserved nucleotide with 2/3 in silico tools (SNPs&GO and Mutation Taster not captured here due to low reliability index and p-value, respectively) predicting a "damaging" outcome. The variant has been observed in the large, broad control population, ExAC, with an allele frequency of 313/121362 (1/387, 2 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic EPCAM variant of 1/35211, suggesting this variant is likely a benign polymorphism. Multiple clinical diagnostic laboratories cite the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	EPCAM: BP4, BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 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. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 28, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 15, 2017	- -

Lynch syndrome Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Mar 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	0.86	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.026	D;D;D
Polyphen		1.0	D;P;.
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

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: rs146480420; hg19: chr2-47601029; COSMIC: COSV104560651; COSMIC: COSV104560651;