rs199473442
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP5_Moderate
The NM_000218.3(KCNQ1):āc.5C>Gā(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2T) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNQ1
NM_000218.3 missense
NM_000218.3 missense
Scores
2
4
13
Clinical Significance
Conservation
PhyloP100: 0.301
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a region_of_interest Disordered (size 27) in uniprot entity KCNQ1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000218.3
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr11-2445103-C-T is described in Lovd as [Pathogenic].
PP5
?
Variant 11-2445103-C-G is Pathogenic according to our data. Variant chr11-2445103-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431053.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.5C>G | p.Ala2Gly | missense_variant | 1/16 | ENST00000155840.12 | |
KCNQ1 | NM_001406836.1 | c.5C>G | p.Ala2Gly | missense_variant | 1/15 | ||
KCNQ1 | NM_001406838.1 | c.5C>G | p.Ala2Gly | missense_variant | 1/11 | ||
KCNQ1 | NM_001406837.1 | c.-358C>G | 5_prime_UTR_variant | 1/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.5C>G | p.Ala2Gly | missense_variant | 1/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000646564.2 | c.5C>G | p.Ala2Gly | missense_variant | 1/11 | ||||
KCNQ1 | ENST00000496887.7 | c.24-280C>G | 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: 940006Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 442668
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
940006
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
442668
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Long QT syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Biotechnology Research Center, Pasteur Institute of Iran | Jul 27, 2017 | According to the ACMG standards and guidelines, the following evidences results in the likely pathogenic variant: Not reported in ExAC and 1000G project and in more than 1000 unrelated Iranian individuals (PM2) but known disease mutation at this position (HGMD ID: CM097076, ClinVar ID: 67091) (PM5) Co segregated with the disease in the family (PP1) Missense variants in KCNQ1 gene are a common mechanism of the LQT1 disease (PP2) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N
MutationTaster
Benign
N
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of MoRF binding (P = 0.1134);
MVP
MPC
ClinPred
T
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