dbSNP rs17036526: EPCAM:c.-149+1G>C (chr2-47345224-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_ModerateBA1

The ENST00000405271.5(EPCAM):c.-149+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 152,102 control chromosomes in the GnomAD database, including 5,239 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 5239 hom., cov: 31)

Exomes 𝑓: 0.13 ( 0 hom. )

Consequence

EPCAM
ENST00000405271.5 splice_donor, intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.634

Publications

8 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 links:

ENSG00000301821 (HGNC:):

ENSG00000301821 links:

EPCAM-DT (HGNC:52639): (EPCAM divergent transcript)

EPCAM-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06413994 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of -25, new splice context is: gggGTgagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM-DT	NR_110207.1 link	n.-150C>G		upstream_gene_variant
EPCAM-DT	NR_110208.1 link	n.-150C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
EPCAM	ENST00000405271.5 link	c.-149+1G>C	splice_donor_variant, intron_variant	Intron 1 of 9	5	ENSP00000385476.1	B5MCA4
EPCAM	ENST00000456133.5 link	n.-149+1G>C	splice_donor_variant, intron_variant	Intron 1 of 10	5	ENSP00000410675.1	B5MCA4
ENSG00000301821	ENST00000782063.1 link	n.374-6751G>C	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.243

AC:

36882

AN:

151890

Hom.:

5224

Cov.:

show subpopulations

Gnomad AFR

AF:

0.385

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.192

Gnomad ASJ

AF:

0.136

Gnomad EAS

AF:

0.315

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.307

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.163

Gnomad OTH

AF:

0.225

GnomAD4 exome

AF:

0.128

AC:

AN:

Hom.:

Cov.:

AF XY:

0.125

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.131

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.243

AC:

36941

AN:

152008

Hom.:

5239

Cov.:

AF XY:

0.249

AC XY:

18471

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.385

AC:

15966

AN:

41474

American (AMR)

AF:

0.192

AC:

2928

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

473

AN:

3466

East Asian (EAS)

AF:

0.315

AC:

1624

AN:

5160

South Asian (SAS)

AF:

0.209

AC:

1006

AN:

4812

European-Finnish (FIN)

AF:

0.307

AC:

3238

AN:

10550

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.163

AC:

11077

AN:

67966

Other (OTH)

AF:

0.222

AC:

469

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1354

2709

4063

5418

6772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.204

Hom.:

441

Bravo

AF:

0.243

Asia WGS

AF:

0.288

AC:

999

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.63

PromoterAI

-0.031

Neutral

(source)

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

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