rs11024034

Variant names:

• chr11-2768933-T-C
• rs11024034
• NM_000218.3:c.1590+14T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000218.3(KCNQ1):​c.1590+14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,605,040 control chromosomes in the GnomAD database, including 9,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (613 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8467 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16
• Conservation: PhyloP100: -0.0630
• Publications: 10 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-2768933-T-C is Benign according to our data. Variant chr11-2768933-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1590+14T>C		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.1494+14T>C		intron	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1320+14T>C		intron	N/A	NP_001393766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1590+14T>C		intron	N/A	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.1209+14T>C		intron	N/A	ENSP00000334497.5
	KCNQ1	ENST00000713725.1		c.1449+14T>C		intron	N/A	ENSP00000519029.1

Frequencies

GnomAD3 genomes AF: 0.0778 AC: 11836 AN: 152076 Hom.: 614 Cov.: 32

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.0648

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0659

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0874

GnomAD2 exomes AF: 0.0861 AC: 21597 AN: 250926 AF XY: 0.0901

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.0458

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.0996

GnomAD4 exome AF: 0.103 AC: 150175 AN: 1452846 Hom.: 8467 Cov.: 30 AF XY: 0.103 AC XY: 74763 AN XY: 723404

African (AFR) AF: 0.0179 AC: 596 AN: 33290

American (AMR) AF: 0.0486 AC: 2174 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3224 AN: 26086

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39666

South Asian (SAS) AF: 0.0759 AC: 6530 AN: 86064

European-Finnish (FIN) AF: 0.107 AC: 5716 AN: 53352

Middle Eastern (MID) AF: 0.126 AC: 700 AN: 5554

European-Non Finnish (NFE) AF: 0.114 AC: 125524 AN: 1104056

Other (OTH) AF: 0.0949 AC: 5701 AN: 60082

GnomAD4 genome AF: 0.0778 AC: 11834 AN: 152194 Hom.: 613 Cov.: 32 AF XY: 0.0770 AC XY: 5732 AN XY: 74408

African (AFR) AF: 0.0203 AC: 844 AN: 41554

American (AMR) AF: 0.0646 AC: 988 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 448 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.0668 AC: 322 AN: 4822

European-Finnish (FIN) AF: 0.100 AC: 1065 AN: 10608

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7781 AN: 67986

Other (OTH) AF: 0.0855 AC: 181 AN: 2116

Alfa AF: 0.0853 Hom.: 306

Bravo AF: 0.0730

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	1	2	not provided (3)
-	-	2	Long QT syndrome (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	Long QT syndrome 1 (1)
-	-	1	Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.78
DANN	Benign	0.54
PhyloP100		-0.063
Mutation Taster		=100/0	polymorphism (auto)

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: rs11024034; hg19: chr11-2790163;