Genetic Variant EPCAM:c.76+5G>C (chr2-47369586-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002354.3(EPCAM):c.76+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,435,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

EPCAM
NM_002354.3 splice_region, intron

Scores

Splicing: ADA: 0.8852

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.941

Publications

1 publications found

Variant links:

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

EPCAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.20740291).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3 link	c.76+5G>C		splice_region_variant, intron_variant	Intron 1 of 8	ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9 link	c.76+5G>C		splice_region_variant, intron_variant	Intron 1 of 8	1	NM_002354.3	ENSP00000263735.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000503

AC:

AN:

198844

AF XY:

0.00000924

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000661

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1435770

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

711780

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32962

American (AMR)

AF:

0.00

AC:

AN:

39912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25454

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38764

South Asian (SAS)

AF:

0.00

AC:

AN:

82148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5220

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101384

Other (OTH)

AF:

0.00

AC:

AN:

59446

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.88

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.065

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.18

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.59

PhyloP100

0.94

PROVEAN

Benign

-0.070

REVEL

Benign

0.087

Sift

Pathogenic

0.0

Sift4G

Benign

0.51

ClinPred

0.13

GERP RS

1.9

PromoterAI

-0.36

Neutral

(source)

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.89

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.51

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.51

Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over