chr2-47375233-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_002354.3(EPCAM):c.426-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000106 in 1,603,194 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 Uncertain significance (★).
Frequency
Consequence
NM_002354.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251198Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135792
GnomAD4 exome AF: 0.00000965 AC: 14AN: 1451046Hom.: 0 Cov.: 29 AF XY: 0.0000125 AC XY: 9AN XY: 722534
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
Congenital diarrhea 5 with tufting enteropathy Pathogenic:1Uncertain:1
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not provided Uncertain:1
Variant summary: The EPCAM c.426-1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a significant impact on normal splicing, which has been shown to occur via Western blot (see Schnell_HMG_2013 below), although this has not been corroborated by RNA studies. This variant was found in the large control database ExAC at a frequency of 0.0000167 (2/119674 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic EPCAM variant (0.0000284). The variant has been identified in at least 1 homozygous patient diagnosed with congenital tufting enteropathy (CTE)(SIVAGNANAM_Gastro_2008), but has not been associated with Lynch syndrome phenotypes in the literature. A functional analysis showed that the variant, which was predicted to cause a deletion of ~20 amino acids that verified by Western blot, impairs proper localization of EPCAM to the plasma membrane (Schnell_HMG_2013). However, the role of this dysfunction in Lynch syndrome development was not established. In addition, two submissions to ClinVar have classified this variant with conflicting interpretations including uncertain significance and pathogenic, though both were submitted under the condition of CTE. Although there is evidence that the variant is deleterious in the context of CTE, there is no data regarding whether the variant is involved in Lynch syndrome phenotype manifestations or not. As such, this variant is classified as VUS specifically in the context of an inherited predisposition to cancers including Lynch syndrome. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at