NM_000218.3:c.1179G>T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 6P and 9B. PS1PM5BP4_StrongBP6BS2
The NM_000218.3(KCNQ1):c.1179G>T(p.Lys393Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000779 in 1,613,974 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K393M) has been classified as Pathogenic.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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KCNQ1 | ENST00000155840.12 | c.1179G>T | p.Lys393Asn | missense_variant | Exon 9 of 16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
KCNQ1 | ENST00000335475.6 | c.798G>T | p.Lys266Asn | missense_variant | Exon 9 of 16 | 1 | ENSP00000334497.5 | |||
KCNQ1 | ENST00000496887.7 | c.822G>T | p.Lys274Asn | missense_variant | Exon 9 of 16 | 5 | ENSP00000434560.2 | |||
KCNQ1 | ENST00000646564.2 | c.639G>T | p.Lys213Asn | missense_variant | Exon 4 of 11 | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes AF: 0.000591 AC: 90AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00109 AC: 275AN: 251370Hom.: 1 AF XY: 0.00126 AC XY: 171AN XY: 135876
GnomAD4 exome AF: 0.000798 AC: 1167AN: 1461660Hom.: 4 Cov.: 32 AF XY: 0.000855 AC XY: 622AN XY: 727146
GnomAD4 genome AF: 0.000591 AC: 90AN: 152314Hom.: 0 Cov.: 33 AF XY: 0.000671 AC XY: 50AN XY: 74468
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:7Other:1
This variant is associated with the following publications: (PMID: 19862833, 25637381, 22949429, 23861362, 31337358, 16556865, 24400285, 23571586, 14661677, 17161064, 14678125, 17210839, 17470695, 19841300, 23396983, 24055113, 25854863, 28074886, 22677073, 30020974, 26970180, 29431662) -
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This variant has been reported in the following publications (PMID:14661677;PMID:14678125;PMID:17161064;PMID:17210839;PMID:17470695;PMID:19841300;PMID:19862833). -
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KCNQ1: BS2 -
Long QT syndrome Uncertain:1Benign:4
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Criteria: BS1 -
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Long QT syndrome 1 Benign:2
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. -
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not specified Benign:2
p.Lys393Asn in exon 9 of KCNQ1: This variant is not expected to have clinical si gnificance because it has been reported in the literature in both control and cl inical cohorts (Ackerman 2003, Moss 2007, Guidicessi 2012, Crotti 2013). In addi tion, this variant has been identified in 0.3% (27/10152) of Ashkenazi Jewish ch romosomes and 0.2% (52/30782) of South Asian chromosomes including 1 homozygote by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; db SNP rs12720457). Studies have shown that the p.Lys393Asn variant does not impact protein function (Shamgar 2006). Furthermore, the lysine (Lys) at amino acid po sition 393 is not conserved across species, including mammals. Of note, cat has an asparagine (Asn) at this position despite high nearby amino acid conservation . Additional computational analyses do not suggest a high likelihood of impact t o the protein. In summary, this variant is classified as likely benign based on the available data. -
Variant summary: The KCNQ1 c.1179G>T (p.Lys393Asn) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 292/277174 control chromosomes, including 1 homozygous individual, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.00266 (27/10152). This frequency is about 27 times the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign. -
Atrial fibrillation, familial, 3 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Jervell and Lange-Nielsen syndrome 1 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Cardiomyopathy Benign:1
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Short QT syndrome type 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Congenital long QT syndrome Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely 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. -
Cardiac arrhythmia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at