chr11-2445250-A-ACGCGCCCAT

Variant names:

• chr11-2445250-A-ACGCGCCCAT
• rs397515877
• NM_000218.3:c.160_168dupATCGCGCCC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. BA1 PM4

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.160_168dup (p.Pro56_Gly57insIleAlaPro) is an in-frame insertion of nine nucleotides within a non-repeat region of KCNQ1 (PM4). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.03002, with 1,854 alleles / 61,766 total alleles in the African/African American population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.004 (BA1). This variant has been reported in at least one affected proband with a diagnosis of long QT syndrome, however, available reported details are not sufficiently specific for long QT syndrome 1, so the PP4 and PS4 codes are not met (PMID:28438721). This variant has been shown to disrupt KCNQ1 function in only one patch-clamp assay, so experimental evidence is not sufficient to meet PS3_Supporting (PMID 19646991). 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: BA1 and PM4. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA006159/MONDO:0100316/112

• Frequency:
  • Genomes: 𝑓 0.0088 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (12 hom.)
• Consequence: KCNQ1 NM_000218.3 conservative_inframe_insertion
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:2 B:11
• Conservation: PhyloP100: -0.203
• Publications: 3 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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM4: 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.160_168dupATCGCGCCC	p.Ile54_Pro56dup	conservative_inframe_insertion	Exon 1 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.160_168dupATCGCGCCC	p.Ile54_Pro56dup	conservative_inframe_insertion	Exon 1 of 15	NP_001393765.1
	KCNQ1	NM_001406838.1		c.160_168dupATCGCGCCC	p.Ile54_Pro56dup	conservative_inframe_insertion	Exon 1 of 11	NP_001393767.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.160_168dupATCGCGCCC	p.Ile54_Pro56dup	conservative_inframe_insertion	Exon 1 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000910997.1		c.160_168dupATCGCGCCC	p.Ile54_Pro56dup	conservative_inframe_insertion	Exon 1 of 16	ENSP00000581056.1
	KCNQ1	ENST00000713725.1		c.160_168dupATCGCGCCC	p.Ile54_Pro56dup	conservative_inframe_insertion	Exon 1 of 15	ENSP00000519029.1	A0AAQ5BGS5

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1305 AN: 148264 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00201

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000135

Gnomad OTH AF: 0.00294

GnomAD2 exomes AF: 0.000258 AC: 2 AN: 7752 AF XY: 0.000207

Gnomad AFR exome AF: 0.00862

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: 0.000311

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000730 AC: 767 AN: 1051082 Hom.: 12 Cov.: 30 AF XY: 0.000659 AC XY: 332 AN XY: 503788

African (AFR) AF: 0.0285 AC: 593 AN: 20828

American (AMR) AF: 0.00195 AC: 15 AN: 7692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12036

East Asian (EAS) AF: 0.00 AC: 0 AN: 20844

South Asian (SAS) AF: 0.0000409 AC: 1 AN: 24432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19226

Middle Eastern (MID) AF: 0.00152 AC: 4 AN: 2638

European-Non Finnish (NFE) AF: 0.0000664 AC: 60 AN: 903282

Other (OTH) AF: 0.00234 AC: 94 AN: 40104

GnomAD4 genome AF: 0.00881 AC: 1307 AN: 148370 Hom.: 21 Cov.: 32 AF XY: 0.00845 AC XY: 612 AN XY: 72398

African (AFR) AF: 0.0308 AC: 1261 AN: 40938

American (AMR) AF: 0.00200 AC: 30 AN: 14964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9276

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000135 AC: 9 AN: 66640

Other (OTH) AF: 0.00291 AC: 6 AN: 2060

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.00371 AC: 12 AN: 3244

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	2	-	Cardiovascular phenotype (2)
1	-	-	Atrial fibrillation, familial, 3 (1)
-	-	1	KCNQ1-related disorder (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 1 (1)
-	-	1	Ventricular fibrillation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.20
Mutation Taster		=34/66	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397515877; hg19: chr11-2466480;