NM_002354.3:c.-98C>G

Variant names:

• chr2-47369408-C-G
• rs528859440
• NM_002354.3:c.-98C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002354.3(EPCAM):​c.-98C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,253,186 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: EPCAM NM_002354.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.658
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-47369408-C-G is Benign according to our data. Variant chr2-47369408-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 336406.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00334 (508/152230) while in subpopulation AFR AF = 0.0116 (482/41558). AF 95% confidence interval is 0.0107. There are 4 homozygotes in GnomAd4. There are 237 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	NM_002354.3	MANE Select	c.-98C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_002345.2	P16422
	EPCAM	NM_002354.3	MANE Select	c.-98C>G		5_prime_UTR	Exon 1 of 9	NP_002345.2	P16422

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPCAM	ENST00000263735.9	TSL:1 MANE Select	c.-98C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000263735.4	P16422
	EPCAM	ENST00000263735.9	TSL:1 MANE Select	c.-98C>G		5_prime_UTR	Exon 1 of 9	ENSP00000263735.4	P16422
	EPCAM	ENST00000895681.1		c.-98C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000565740.1

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 508 AN: 152122 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.000324 AC: 357 AN: 1100956 Hom.: 1 Cov.: 16 AF XY: 0.000288 AC XY: 154 AN XY: 535610

African (AFR) AF: 0.0140 AC: 305 AN: 21766

American (AMR) AF: 0.000323 AC: 3 AN: 9284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16146

East Asian (EAS) AF: 0.00 AC: 0 AN: 26998

South Asian (SAS) AF: 0.00 AC: 0 AN: 48646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29514

Middle Eastern (MID) AF: 0.000311 AC: 1 AN: 3218

European-Non Finnish (NFE) AF: 0.0000122 AC: 11 AN: 899100

Other (OTH) AF: 0.000799 AC: 37 AN: 46284

GnomAD4 genome AF: 0.00334 AC: 508 AN: 152230 Hom.: 4 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74424

African (AFR) AF: 0.0116 AC: 482 AN: 41558

American (AMR) AF: 0.000784 AC: 12 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67998

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00388

Asia WGS AF: 0.000580 AC: 2 AN: 3462

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		0.66
PromoterAI		0.036	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs528859440; hg19: chr2-47596547;