11-2445250-A-ACGCGCCCAT

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_000218.3(KCNQ1):c.160_168dup(p.Ile54_Pro56dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,199,452 control chromosomes in the GnomAD database, including 33 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0088 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (12 hom.)
• Consequence: KCNQ1 NM_000218.3 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:8
• Conservation: PhyloP100: -0.203

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000218.3.
• BP6: Variant 11-2445250-A-ACGCGCCCAT is Benign according to our data. Variant chr11-2445250-A-ACGCGCCCAT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42487.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=4, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00881 (1307/148370) while in subpopulation AFR AF= 0.0308 (1261/40938). AF 95% confidence interval is 0.0294. There are 21 homozygotes in gnomad4. There are 612 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.160_168dup	p.Ile54_Pro56dup	inframe_insertion	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.160_168dup	p.Ile54_Pro56dup	inframe_insertion	1/15
KCNQ1	NM_001406838.1	c.160_168dup	p.Ile54_Pro56dup	inframe_insertion	1/11
KCNQ1	NM_001406837.1	c.-203_-195dup		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.160_168dup	p.Ile54_Pro56dup	inframe_insertion	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000646564.2	c.160_168dup	p.Ile54_Pro56dup	inframe_insertion	1/11
KCNQ1	ENST00000496887.7	c.24-125_24-117dup		intron_variant		5

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

GnomAD3 exomes AF: 0.000258 AC: 2 AN: 7752 Hom.: 0 AF XY: 0.000207 AC XY: 1 AN XY: 4828

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 SAS 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

Gnomad4 AFR exome AF: 0.0285

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000409

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000664

Gnomad4 OTH exome AF: 0.00234

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

Gnomad4 AFR AF: 0.0308

Gnomad4 AMR AF: 0.00200

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000135

Gnomad4 OTH AF: 0.00291

Asia WGS AF: 0.00371 AC: 12 AN: 3244

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2022	Variant summary: KCNQ1 c.160_168dupATCGCGCCC (p.Ile54_Pro56dup) results in an in-frame duplication that is predicted to duplicate 3 amino acids into the encoded protein. The variant allele was found at a frequency of 0.0073 in 35616 control chromosomes, predominantly at a frequency of 0.03 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 300 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.160_168dupATCGCGCCC has been reported in the literature in individuals affected with Arrhythmia as well as in control population (e.g. Abraham_2010, Berge_2008, Ackerman_2003, Tester_2005_01, Kapa_2009, Hassnan_2017, Millat_2014). In a family with familial atrial fibrillation, this variant was found in four affected members and also in an unaffected carrier suggesting an inconclusive co-segregation of this variant with disease (Abraham_2010). This family however, was not comprehensively screened for mutations in all susceptibility genes. Co-occurrences with other pathogenic variants have been reported (KCNQ1 c.674C>T, p.Ser225Leu; KCNH2 c.1841C>T, p.Ala614Val) in our internal database. In vitro functional study detected partial defect of the channel properties (Abraham_2010), suggesting that it could be a functional polymorphism. Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=1) or benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2017	p.Ile54_Pro56dup in Exon 1 of KCNQ1: This variant is not expected to have clinic al significance because it has been identified in 2.9% (250/8370) of African ch romosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs561562768). It has been reported in two individuals with cardia c arrhythmias (1/182 LQTS, Berge 2008; 1/231 AF, Abraham 2010) and segregated in three affected individuals in one family, though phenotypes were unknown in 2 o ther mutation carriers (Abraham 2010). In addition, one study demonstrated some alteration of channel properties (Abraham 2010) although this study was only in vitro such that correlation to a clinical phenotype was not possible. This varia nt was also identified in several healthy control cohorts (0.3% 4/1488 chromosom es, Ackerman 2003; 1/364 chromosomes, Arnestad 2007; 2.1% (2/94) African-America n control chromosomes, Abraham 2010) and is now listed in the KCNQ1 database as a benign variant (http://www.fsm.it/cardmoc/kvlqt1poly.htm). In summary, given t he high frequency of the variant in spite of the reports in the literature, this variant is benign for a reasonably penetrant disease variant and insufficient b iological evidence for a clinically relevant impact to protein function, we have classified this variant as likely benign. -

Cardiovascular phenotype Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 27, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2013	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	This variant is associated with the following publications: (PMID: 18752142, 14661677, 17210839, 19646991, 28438721, 32048431, 30847666) -

Atrial fibrillation, familial, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2010

- -

KCNQ1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ventricular fibrillation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 20, 2019

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515877; hg19: chr11-2466480;