ENST00000405271:c.-15A>G

Variant names:

• chr2-47369061-A-G
• rs78212572
• ENST00000405271.5:c.-15A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000405271.5(EPCAM):​c.-15A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,372,606 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (26 hom.)
• Consequence: EPCAM ENST00000405271.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.623
• Publications: 2 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 (BayesDel_noAF=-0.82).
• BP6: Variant 2-47369061-A-G is Benign according to our data. Variant chr2-47369061-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1217191.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 = 0.00978 (1488/152156) while in subpopulation AFR AF = 0.0321 (1335/41534). AF 95% confidence interval is 0.0307. There are 30 homozygotes in GnomAd4. There are 684 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000405271.5. 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.-445A>G		upstream_gene	N/A	NP_002345.2	P16422

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	ENST00000405271.5	TSL:5	c.-15A>G		5_prime_UTR	Exon 2 of 10	ENSP00000385476.1	B5MCA4
	EPCAM	ENST00000456133.5	TSL:5	n.-15A>G		non_coding_transcript_exon	Exon 2 of 11	ENSP00000410675.1	B5MCA4
	EPCAM	ENST00000456133.5	TSL:5	n.-15A>G		5_prime_UTR	Exon 2 of 11	ENSP00000410675.1	B5MCA4

Frequencies

GnomAD3 genomes AF: 0.00977 AC: 1485 AN: 152038 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00108 AC: 28 AN: 25890 AF XY: 0.000659

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000880

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.00116 AC: 1421 AN: 1220450 Hom.: 26 Cov.: 30 AF XY: 0.00108 AC XY: 633 AN XY: 588678

African (AFR) AF: 0.0368 AC: 871 AN: 23692

American (AMR) AF: 0.00515 AC: 47 AN: 9122

Ashkenazi Jewish (ASJ) AF: 0.000342 AC: 6 AN: 17522

East Asian (EAS) AF: 0.00 AC: 0 AN: 27010

South Asian (SAS) AF: 0.000102 AC: 5 AN: 49258

European-Finnish (FIN) AF: 0.0000230 AC: 1 AN: 43454

Middle Eastern (MID) AF: 0.00417 AC: 21 AN: 5034

European-Non Finnish (NFE) AF: 0.000309 AC: 308 AN: 995334

Other (OTH) AF: 0.00324 AC: 162 AN: 50024

GnomAD4 genome AF: 0.00978 AC: 1488 AN: 152156 Hom.: 30 Cov.: 32 AF XY: 0.00919 AC XY: 684 AN XY: 74398

African (AFR) AF: 0.0321 AC: 1335 AN: 41534

American (AMR) AF: 0.00582 AC: 89 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10592

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67976

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.00536 Hom.: 3

Bravo AF: 0.0116

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.32
PhyloP100		-0.62
PromoterAI		0.026	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs78212572; hg19: chr2-47596200;