rs78608315

Variant names:

• chr2-47377009-T-C
• rs78608315
• NM_002354.3:c.492-5T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-47377009-T-C
• chr2-47377009-T-G

Variant summary

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

The NM_002354.3(EPCAM):​c.492-5T>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 0.0301 in 1,592,016 control chromosomes in the GnomAD database, including 908 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (78 hom., cov: 31)
  • Exomes 𝑓: 0.031 (830 hom.)
• Consequence: EPCAM NM_002354.3 splice_region, intron
• Scores: Splicing: ADA: 0.02180
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.58
• Publications: 7 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), PanelApp Australia, Orphanet, G2P, Ambry Genetics
• 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=-0.48).
• BP6: Variant 2-47377009-T-C is Benign according to our data. Variant chr2-47377009-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0247 (3759/152270) while in subpopulation NFE AF = 0.0368 (2503/68012). AF 95% confidence interval is 0.0356. There are 78 homozygotes in GnomAd4. There are 1894 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002354.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	NM_002354.3	MANE Select	c.492-5T>C		splice_region intron	N/A	NP_002345.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	ENST00000263735.9	TSL:1 MANE Select	c.492-5T>C		splice_region intron	N/A	ENSP00000263735.4
	EPCAM	ENST00000405271.5	TSL:5	c.576-5T>C		splice_region intron	N/A	ENSP00000385476.1
	EPCAM	ENST00000456133.5	TSL:5	n.576-5T>C		splice_region intron	N/A	ENSP00000410675.1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3760 AN: 152152 Hom.: 78 Cov.: 31

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0368

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0248 AC: 6237 AN: 251224 AF XY: 0.0249

Gnomad AFR exome AF: 0.00573

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.0359

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0306 AC: 44099 AN: 1439746 Hom.: 830 Cov.: 27 AF XY: 0.0299 AC XY: 21487 AN XY: 717844

African (AFR) AF: 0.00492 AC: 163 AN: 33106

American (AMR) AF: 0.0119 AC: 534 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 274 AN: 26008

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39580

South Asian (SAS) AF: 0.00604 AC: 519 AN: 85886

European-Finnish (FIN) AF: 0.0539 AC: 2870 AN: 53294

Middle Eastern (MID) AF: 0.00628 AC: 36 AN: 5732

European-Non Finnish (NFE) AF: 0.0349 AC: 38113 AN: 1091778

Other (OTH) AF: 0.0266 AC: 1587 AN: 59656

GnomAD4 genome AF: 0.0247 AC: 3759 AN: 152270 Hom.: 78 Cov.: 31 AF XY: 0.0254 AC XY: 1894 AN XY: 74466

African (AFR) AF: 0.00563 AC: 234 AN: 41550

American (AMR) AF: 0.0179 AC: 273 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4830

European-Finnish (FIN) AF: 0.0577 AC: 612 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0368 AC: 2503 AN: 68012

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.0254 Hom.: 29

Bravo AF: 0.0203

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0343

EpiControl AF: 0.0340

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Lynch syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.61
PhyloP100		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.022
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -13

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

Other links and lift over

dbSNP: rs78608315; hg19: chr2-47604148; COSMIC: COSV104560627;