Variant rs199472778 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000218.3(KCNQ1):c.1265A>C(p.Lys422Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K422R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 4.38

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]

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1265A>C	p.Lys422Thr	missense_variant	10/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1265A>C	p.Lys422Thr	missense_variant	10/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.884A>C	p.Lys295Thr	missense_variant	10/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.908A>C	p.Lys303Thr	missense_variant	10/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.725A>C	p.Lys242Thr	missense_variant	5/11			ENSP00000495806

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250928

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461426

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 11, 2024

- -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:20541041). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;.;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;.;N

REVEL

Pathogenic

0.69

Sift

Benign

0.25

T;.;T

Sift4G

Benign

0.48

T;.;T

Polyphen

0.23

B;.;P

Vest4

0.80

MutPred

0.36

Loss of sheet (P = 0.0054);.;.;

MVP

0.96

MPC

0.67

ClinPred

0.73

GERP RS

5.0

Varity_R

0.15

gMVP

0.66

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over