11-2736755-C-T

Variant names:

• chr11-2736755-C-T
• rs108961
• NM_000218.3:c.1515-32089C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000218.3(KCNQ1):​c.1515-32089C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 152,214 control chromosomes in the GnomAD database, including 14,831 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (14831 hom., cov: 34)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.503 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.1515-32089C>T		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.1419-32089C>T		intron	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1245-32089C>T		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.1515-32089C>T		intron	N/A	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.1134-32089C>T		intron	N/A	ENSP00000334497.5
	KCNQ1	ENST00000713725.1		c.1374-32089C>T		intron	N/A	ENSP00000519029.1

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65897 AN: 152096 Hom.: 14817 Cov.: 34

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.597

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.458

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.433 AC: 65936 AN: 152214 Hom.: 14831 Cov.: 34 AF XY: 0.421 AC XY: 31324 AN XY: 74416

African (AFR) AF: 0.508 AC: 21109 AN: 41532

American (AMR) AF: 0.375 AC: 5735 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1476 AN: 3464

East Asian (EAS) AF: 0.208 AC: 1076 AN: 5178

South Asian (SAS) AF: 0.393 AC: 1898 AN: 4828

European-Finnish (FIN) AF: 0.266 AC: 2820 AN: 10604

Middle Eastern (MID) AF: 0.507 AC: 148 AN: 292

European-Non Finnish (NFE) AF: 0.444 AC: 30166 AN: 67994

Other (OTH) AF: 0.456 AC: 965 AN: 2116

Alfa AF: 0.445 Hom.: 29020

Bravo AF: 0.446

Asia WGS AF: 0.322 AC: 1121 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.066
DANN	Benign	0.57
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs108961; hg19: chr11-2757985; COSMIC: COSV50102879;