rs143709408

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP5BS1

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.458C>T is a missense variant predicted to cause substitution of threonine by methionine at amino acid 153 (p.Thr153Met). This variant has been observed in 1 patient with an alternate molecular basis for disease with a phenotype that is not sufficiently specific. The patient has a KCNH2 variant, p.Arg752Trp, that is P/LP in ClinVar. (BP5; PMID:28794082). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0006396, with 48 alleles / 75052 total alleles in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 (BS1). In summary, this variant meets the criteria to be classified as likely benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BP5, BS1. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA007144/MONDO:0100316/112

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:6B:5O:1

Conservation

PhyloP100: 2.19

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 1
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Jervell and Lange-Nielsen syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
atrial fibrillation, familial, 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
short QT syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
short QT syndrome type 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNQ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ1	NM_000218.3	MANE Select	c.458C>T	p.Thr153Met	missense	Exon 2 of 16	NP_000209.2
KCNQ1	NM_001406836.1		c.458C>T	p.Thr153Met	missense	Exon 2 of 15	NP_001393765.1
KCNQ1	NM_001406837.1		c.188C>T	p.Thr63Met	missense	Exon 3 of 17	NP_001393766.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.458C>T	p.Thr153Met	missense	Exon 2 of 16	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6	TSL:1	c.77C>T	p.Thr26Met	missense	Exon 2 of 16	ENSP00000334497.5	P51787-2
KCNQ1	ENST00000910997.1		c.458C>T	p.Thr153Met	missense	Exon 2 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000159

AC:

AN:

251312

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000136

AC:

199

AN:

1461358

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33474

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000146

AC:

162

AN:

1111734

Other (OTH)

AF:

0.000116

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000355

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000697

AC:

AN:

41578

American (AMR)

AF:

0.000327

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000207

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome (4)

not provided (3)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

Long QT syndrome 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

CardioboostArm

Uncertain

0.55

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

Eigen

Benign

0.091

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.21

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.7

PhyloP100

2.2

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.74

Sift

Benign

0.071

Sift4G

Benign

0.093

Polyphen

0.88

Vest4

0.81

MVP

0.96

MPC

1.2

ClinPred

0.023

GERP RS

3.5

Varity_R

0.099

gMVP

0.87

Mutation Taster

=22/78

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over