rs199473485
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000218.3(KCNQ1):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNQ1
NM_000218.3 start_lost
NM_000218.3 start_lost
Scores
7
2
7
Clinical Significance
Conservation
PhyloP100: 0.379
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 Pathogenic. Variant got 12 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-2445100-T-A is Pathogenic according to our data. Variant chr11-2445100-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 488859.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.2T>A | p.Met1? | start_lost | 1/16 | ENST00000155840.12 | |
KCNQ1 | NM_001406836.1 | c.2T>A | p.Met1? | start_lost | 1/15 | ||
KCNQ1 | NM_001406838.1 | c.2T>A | p.Met1? | start_lost | 1/11 | ||
KCNQ1 | NM_001406837.1 | c.-361T>A | 5_prime_UTR_variant | 1/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.2T>A | p.Met1? | start_lost | 1/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000646564.2 | c.2T>A | p.Met1? | start_lost | 1/11 | ||||
KCNQ1 | ENST00000496887.7 | c.24-283T>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 936200Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 440548
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
936200
Hom.:
Cov.:
30
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AC XY:
0
AN XY:
440548
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2016 | Although the c.2 T>A pathogenic variant in the KCNQ1 gene has not been published to our knowledge, another pathogenic variant affecting the same nucleotide, c.2 T>C, has been reported previously in association with JLNS and LQTS (Wang et al., 2011; Gao et al., 2016). Wang et al. (2011) reported c.2 T>C, situated on opposite KCNQ1 alleles (in trans) from a pathogenic frameshift variant, in one individual with JLNS. This individual's father, who was asymptomatic but had a borderline prolonged QTc interval, also harbored c.2 T>C (Wang et al., 2011). Subsequently, Gao et al (2015) identified c.2 T>C in three Chinese individuals with LQTS, and reported it was absent in at least 100 ethnically matched, healthy control alleles. Data from control individuals was not available to assess whether c.2 T>A may be a common benign variant in the general population. Both the c.2 T>A variant and the c.2 T>C variant alter the initiator Methionine residue of KCNQ1. Western blot studies showed that c.2 T>C may cause an alternate translation initiation site downstream and yields a truncated protein that is missing the initial 158 amino acid residues of the KCNQ1 protein (Wang et al., 2011). Additional functional studies showed that while the c.2 T>C variant does not demonstrate a dominant negative effect when co-expressed with wild type protein, it does result in loss of function of the KCNQ1 channel due to a trafficking defect (Wang et al., 2011).In summary, c.2 T>A in the KCNQ1 gene is interpreted as a pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
B
Vest4
MutPred
Gain of ubiquitination at M1 (P = 0.0177);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at