rs28730752
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000218.3(KCNQ1):c.478-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00857 in 1,612,094 control chromosomes in the GnomAD database, including 961 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.045 ( 492 hom., cov: 33)
Exomes 𝑓: 0.0047 ( 469 hom. )
Consequence
KCNQ1
NM_000218.3 splice_polypyrimidine_tract, intron
NM_000218.3 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00003238
2
Clinical Significance
Conservation
PhyloP100: 0.611
Genes affected
KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 11-2570618-G-A is Benign according to our data. Variant chr11-2570618-G-A is described in ClinVar as [Benign]. Clinvar id is 42490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570618-G-A is described in Lovd as [Benign]. Variant chr11-2570618-G-A is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| KCNQ1 | NM_000218.3 | c.478-10G>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000155840.12 | NP_000209.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KCNQ1 | ENST00000155840.12 | c.478-10G>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000218.3 | ENSP00000155840 | P1 | |||
| KCNQ1 | ENST00000335475.6 | c.97-10G>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | ENSP00000334497 | |||||
| KCNQ1 | ENST00000496887.7 | c.217-10G>A | splice_polypyrimidine_tract_variant, intron_variant | 5 | ENSP00000434560 | |||||
| KCNQ1 | ENST00000646564.2 | c.478-12817G>A | intron_variant | ENSP00000495806 |
Frequencies
GnomAD3 genomes 0.0452 AC: 6877AN: 152196Hom.: 486 Cov.: 33
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GnomAD3 exomes AF: 0.0117 AC: 2921AN: 249002Hom.: 210 AF XY: 0.00815 AC XY: 1101AN XY: 135042
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GnomAD4 exome AF: 0.00474 AC: 6920AN: 1459780Hom.: 469 Cov.: 32 AF XY: 0.00410 AC XY: 2977AN XY: 726302
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GnomAD4 genome 0.0453 AC: 6901AN: 152314Hom.: 492 Cov.: 33 AF XY: 0.0436 AC XY: 3247AN XY: 74468
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ClinVar
Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | 478-10G>A in Intron 02 of KCNQ1: This variant is not expected to have clinical s ignificance because it has been identified in 14.7% (549/3734) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs28730752). - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Long QT syndrome 1 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Atrial fibrillation, familial, 3 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Jervell and Lange-Nielsen syndrome 1 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Short QT syndrome type 2 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Congenital long QT syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Long QT syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Cardiac arrhythmia Benign:1
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 19, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at