7-150945350-C-T
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The NM_000238.4(KCNH2):c.*15G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,582,518 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000238.4 3_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.*15G>A | 3_prime_UTR_variant | Exon 15 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186 | c.*15G>A | 3_prime_UTR_variant | Exon 15 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | |||
KCNH2 | ENST00000330883 | c.*15G>A | 3_prime_UTR_variant | Exon 11 of 11 | 1 | ENSP00000328531.4 | ||||
KCNH2 | ENST00000684241.1 | n.4328G>A | non_coding_transcript_exon_variant | Exon 13 of 13 |
Frequencies
GnomAD3 genomes AF: 0.0114 AC: 1736AN: 152168Hom.: 33 Cov.: 33
GnomAD3 exomes AF: 0.00262 AC: 522AN: 199372Hom.: 13 AF XY: 0.00195 AC XY: 211AN XY: 108244
GnomAD4 exome AF: 0.00112 AC: 1597AN: 1430234Hom.: 34 Cov.: 31 AF XY: 0.000949 AC XY: 672AN XY: 708458
GnomAD4 genome AF: 0.0114 AC: 1735AN: 152284Hom.: 33 Cov.: 33 AF XY: 0.0110 AC XY: 820AN XY: 74458
ClinVar
Submissions by phenotype
not provided Benign:3
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Long QT syndrome 2 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not specified Benign:1
Variant summary: KCNH2 c.*15G>A is located in the untranslated mRNA region downstream of the termination codon. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0026 in 199372 control chromosomes in the gnomAD database, including 13 homozygotes. The observed variant frequency is approximately 26 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.*15G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Cardiovascular phenotype Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at