chr2-47375300-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_002354.3(EPCAM):c.491+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000181 in 1,602,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_002354.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251214Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135780
GnomAD4 exome AF: 0.0000179 AC: 26AN: 1450332Hom.: 0 Cov.: 27 AF XY: 0.0000208 AC XY: 15AN XY: 722384
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
Congenital diarrhea 5 with tufting enteropathy Pathogenic:2
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PVS1;PM2;PM3;PP1;PP3;PP4 -
Gastric cancer Pathogenic:1
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Hereditary cancer-predisposing syndrome Pathogenic:1
The c.491+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the EPCAM gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function. Based on data from gnomAD, the A allele has an overall frequency of 0.0056% (14/251,214) total alleles studied. The highest observed frequency was 0.03% (11/34,570) of Latino alleles. This alteration was reported homozygous or compound heterozygous with a second mutation in EPCAM in multiple patients with failure to thrive, diarrhea, vomiting, and endoscopic duodenal biopsies with characteristic histology consistent with congenital tufting enteropathy (Sivagnanam, 2008; Ko, 2010; Fang, 2020). This nucleotide position is highly conserved in available vertebrate species. Reverse-transcription polymerase chain reaction of duodenal tissue demonstrated a novel alternative splice form with deletion of exon 4 (Sivagnanam, 2008). Mutant mice with universal Epcam exon 4 deletion showed widespread epithelial dysplasia, intestinal failure, and limited life spans with a dramatic lack of weight gain compared with wildtype mice (Mueller, 2014). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -
not provided Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at