rs199473671

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000218.3(KCNQ1):c.136G>A(p.Ala46Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000673 in 1,143,396 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. A46E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9O:1

Conservation

PhyloP100: 0.596

Publications

11 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: Uncertain_significance. The variant received 1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.

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.136G>A	p.Ala46Thr	missense	Exon 1 of 16	NP_000209.2
KCNQ1	NM_001406836.1		c.136G>A	p.Ala46Thr	missense	Exon 1 of 15	NP_001393765.1
KCNQ1	NM_001406838.1		c.136G>A	p.Ala46Thr	missense	Exon 1 of 11	NP_001393767.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.136G>A	p.Ala46Thr	missense	Exon 1 of 16	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000910997.1		c.136G>A	p.Ala46Thr	missense	Exon 1 of 16	ENSP00000581056.1
KCNQ1	ENST00000713725.1		c.136G>A	p.Ala46Thr	missense	Exon 1 of 15	ENSP00000519029.1	A0AAQ5BGS5

Frequencies

GnomAD3 genomes

AF:

0.0000742

AC:

AN:

148180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000165

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000600

AC:

AN:

16670

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000163

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000663

AC:

AN:

995216

Hom.:

Cov.:

AF XY:

0.0000588

AC XY:

AN XY:

476588

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19306

American (AMR)

AF:

0.00

AC:

AN:

8196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10502

East Asian (EAS)

AF:

0.00

AC:

AN:

14480

South Asian (SAS)

AF:

0.00

AC:

AN:

25512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14724

Middle Eastern (MID)

AF:

0.000418

AC:

AN:

2392

European-Non Finnish (NFE)

AF:

0.0000741

AC:

AN:

863946

Other (OTH)

AF:

0.0000277

AC:

AN:

36158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.560

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:

0.0000742

AC:

AN:

148180

Hom.:

Cov.:

AF XY:

0.0000416

AC XY:

AN XY:

72154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41004

American (AMR)

AF:

0.00

AC:

AN:

14932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3398

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000165

AC:

AN:

66472

Other (OTH)

AF:

0.00

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.00

Hom.:

Bravo

AF:

0.0000945

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 (1)

Cardiovascular phenotype (1)

Long QT syndrome (1)

Long QT syndrome 1 (1)

not specified (1)

Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

CardioboostArm

Benign

0.0027

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.41

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.59

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

0.55

PhyloP100

0.60

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.20

REVEL

Uncertain

0.52

Sift

Benign

0.28

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.67

MVP

0.88

MPC

1.1

ClinPred

0.055

GERP RS

1.4

PromoterAI

-0.080

Neutral

(source)

Varity_R

0.035

gMVP

0.26

Mutation Taster

=31/69

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