rs28730664

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1BP4BP7

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.477+9C>T is a variant in intron 2. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.03492 (2612 / 74792 alleles, with 48 homozygotes) in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.001 (BA1). The computational splicing predictor SpliceAI gives this silent variant a delta score of 0.1 for donor loss which is below the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and does not strongly predict a splicing defect (BP4). This intronic variant is not located within either of the regions immediately flanking the exon (between +1 and +7 or between -1 and -21), and the conservation tool PhyloP gives this variant a score of -2.693, which is below the Potassium Channel Arrhythmia VCEP BP7 threshold of <2.0 and indicates a low level of evolutionary conservation at this site (BP7). In summary, this variant meets the criteria to be classified as benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BA1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA007191/MONDO:0100316/112

Frequency

Genomes: 𝑓 0.011 ( 25 hom., cov: 34)

Exomes 𝑓: 0.0024 ( 53 hom. )

Consequence

KCNQ1
NM_000218.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: -2.68

Publications

2 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
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: Benign. The variant received -10 ACMG points.

BP4

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

BP7

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.477+9C>T		intron_variant	Intron 2 of 15	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 link	c.477+9C>T		intron_variant	Intron 2 of 15	1	NM_000218.3	ENSP00000155840.2		P51787-1

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1612

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00481

Gnomad SAS

AF:

0.0232

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00573

AC:

1438

AN:

250742

AF XY:

0.00576

show subpopulations

Gnomad AFR exome

AF:

0.0380

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00517

Gnomad FIN exome

AF:

0.0000477

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00236

AC:

3423

AN:

1450574

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

1929

AN XY:

722410

show subpopulations

African (AFR)

AF:

0.0362

AC:

1202

AN:

33216

American (AMR)

AF:

0.00161

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000767

AC:

AN:

26066

East Asian (EAS)

AF:

0.00378

AC:

150

AN:

39640

South Asian (SAS)

AF:

0.0179

AC:

1544

AN:

86018

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52370

Middle Eastern (MID)

AF:

0.00313

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000158

AC:

174

AN:

1102790

Other (OTH)

AF:

0.00403

AC:

242

AN:

60014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

204

408

613

817

1021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.0106

AC:

1618

AN:

152344

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

817

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0339

AC:

1410

AN:

41576

American (AMR)

AF:

0.00216

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00482

AC:

AN:

5184

South Asian (SAS)

AF:

0.0232

AC:

112

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68028

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

157

235

314

392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00623

Hom.:

Bravo

AF:

0.0114

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

477+9C>T in Intron 02 of KCNQ1: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce and has been identified in 3.6% (135/3738) of African American chromosomes f rom a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS; dbSNP rs28730664). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome 1

Benign:2

Jul 01, 2025

ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_000218.3(KCNQ1):c.477+9C>T is a variant in intron 2. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.03492 (2612 / 74792 alleles, with 48 homozygotes) in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.001 (BA1). The computational splicing predictor SpliceAI gives this silent variant a delta score of 0.1 for donor loss which is below the ClinGen Potassium Channel Arrhythmia VCEP BP4 threshold of <0.2 and does not strongly predict a splicing defect (BP4). This intronic variant is not located within either of the regions immediately flanking the exon (between +1 and +7 or between -1 and -21), and the conservation tool PhyloP gives this variant a score of -2.693, which is below the Potassium Channel Arrhythmia VCEP BP7 threshold of <2.0 and indicates a low level of evolutionary conservation at this site (BP7). In summary, this variant meets the criteria to be classified as benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: BA1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 03/04/2025). -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atrial fibrillation, familial, 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jervell and Lange-Nielsen syndrome 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Short QT syndrome type 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital long QT syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.18

(source)

DANN

Benign

0.58

PhyloP100

-2.7

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over