rs28730664

Variant names:

• chr11-2528027-C-T
• rs28730664
• NM_000218.3:c.477+9C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP4 BP7

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
• Clinical Significance: Benign reviewed by expert panel B:13
• Conservation: PhyloP100: -2.68
• Publications: 2 publications found

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

ACMG classification

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.477+9C>T		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.477+9C>T		intron	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.207+9C>T		intron	N/A	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.477+9C>T		intron	N/A	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.96+9C>T		intron	N/A	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.477+9C>T		intron	N/A	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1612 AN: 152226 Hom.: 25 Cov.: 34

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

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.: 53 Cov.: 29 AF XY: 0.00267 AC XY: 1929 AN XY: 722410

African (AFR) AF: 0.0362 AC: 1202 AN: 33216

American (AMR) AF: 0.00161 AC: 72 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000767 AC: 20 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: 1 AN: 52370

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5746

European-Non Finnish (NFE) AF: 0.000158 AC: 174 AN: 1102790

Other (OTH) AF: 0.00403 AC: 242 AN: 60014

GnomAD4 genome AF: 0.0106 AC: 1618 AN: 152344 Hom.: 25 Cov.: 34 AF XY: 0.0110 AC XY: 817 AN XY: 74504

African (AFR) AF: 0.0339 AC: 1410 AN: 41576

American (AMR) AF: 0.00216 AC: 33 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00482 AC: 25 AN: 5184

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68028

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00623 Hom.: 2

Bravo AF: 0.0114

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Long QT syndrome 1 (2)
-	-	2	not provided (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	Long QT syndrome (1)
-	-	1	Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.18
DANN	Benign	0.58
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs28730664; hg19: chr11-2549257; COSMIC: COSV107232977; COSMIC: COSV107232977;