11-2572943-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_000218.3(KCNQ1):​c.878G>T​(p.Arg293Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R293C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNQ1
NM_000218.3 missense

Scores

3
6
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0700
Variant links:
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-2572942-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.878G>T p.Arg293Leu missense_variant 6/16 ENST00000155840.12 NP_000209.2 P51787-1Q96AI9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.878G>T p.Arg293Leu missense_variant 6/161 NM_000218.3 ENSP00000155840.2 P51787-1
KCNQ1ENST00000335475.6 linkuse as main transcriptc.497G>T p.Arg166Leu missense_variant 6/161 ENSP00000334497.5 P51787-2
KCNQ1ENST00000496887.7 linkuse as main transcriptc.617G>T p.Arg206Leu missense_variant 7/165 ENSP00000434560.2 E9PPZ0
KCNQ1ENST00000646564.2 linkuse as main transcriptc.478-10492G>T intron_variant ENSP00000495806.2 A0A2R8YEQ9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.070
CADD
Benign
8.2
DANN
Benign
0.95
DEOGEN2
Pathogenic
0.91
D;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.038
N
LIST_S2
Benign
0.67
T;T
M_CAP
Pathogenic
0.47
D
MetaRNN
Uncertain
0.55
D;D
MetaSVM
Uncertain
0.43
D
MutationAssessor
Benign
1.6
L;.
PrimateAI
Benign
0.30
T
PROVEAN
Uncertain
-3.4
D;D
REVEL
Uncertain
0.60
Sift
Uncertain
0.018
D;D
Sift4G
Benign
0.065
T;D
Polyphen
0.0030
B;B
Vest4
0.41
MutPred
0.71
Loss of disorder (P = 0.0251);.;
MVP
0.74
MPC
0.47
ClinPred
0.25
T
GERP RS
-3.1
Varity_R
0.38
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199473465; hg19: chr11-2594173; API