chr11-2611922-A-G

Variant names:

• chr11-2611922-A-G
• rs10766212
• ENST00000597346.1:n.88073T>C

Variant summary

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

The ENST00000597346.1(KCNQ1OT1):​n.88073T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 398,284 control chromosomes in the GnomAD database, including 66,594 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 0.53 (22666 hom., cov: 32)
  • Exomes 𝑓: 0.59 (43928 hom.)
• Consequence: KCNQ1OT1 ENST00000597346.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.244
• Publications: 14 publications found

Genes affected

KCNQ1OT1 (HGNC:6295): (KCNQ1 opposite strand/antisense transcript 1) Human chromosomal region 11p15.5 contains two clusters of epigenetically-regulated genes that are expressed from only one chromosome in a parent-of-origin manner. Each cluster, or imprinted domain, is regulated by a functionally independent imprinting control region (ICR). The human CDKN1C/KCNQ1OT1 domain is regulated by an ICR located in an intron of KCNQ1, and contains at least eight genes that are expressed exclusively or preferentially from the maternally-inherited allele. The DNA of the ICR is specifically methylated on the maternally-inherited chromosome, and unmethylated on the paternally-inherited chromosome. The ICR contains the promoter of the KCNQ1OT1 gene that is exclusively expressed from the paternal allele. The KCNQ1OT1 transcript is the antisense to the KCNQ1 gene and is a unspliced long non-coding RNA. It interacts with chromatin and regulates transcription of multiple target genes through epigenetic modifications. The transcript is abnormally expressed from both chromosomes in most patients with Beckwith-Wiedemann syndrome, and the transcript also plays an important role in colorectal carcinogenesis. [provided by RefSeq, Apr 2012]

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000597346.1. 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
	KCNQ1OT1	NR_002728.4	MANE Select	n.88073T>C		non_coding_transcript_exon	Exon 1 of 1
	KCNQ1	NM_000218.3	MANE Select	c.1393+23068A>G		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.1297+23068A>G		intron	N/A	NP_001393765.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1OT1	ENST00000597346.1	TSL:6 MANE Select	n.88073T>C		non_coding_transcript_exon	Exon 1 of 1
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1393+23068A>G		intron	N/A	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.1012+23068A>G		intron	N/A	ENSP00000334497.5

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80930 AN: 151928 Hom.: 22658 Cov.: 32

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.535

GnomAD4 exome AF: 0.592 AC: 145890 AN: 246238 Hom.: 43928 Cov.: 0 AF XY: 0.592 AC XY: 73906 AN XY: 124764

African (AFR) AF: 0.355 AC: 2546 AN: 7178

American (AMR) AF: 0.527 AC: 3917 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 4709 AN: 9238

East Asian (EAS) AF: 0.741 AC: 16956 AN: 22868

South Asian (SAS) AF: 0.639 AC: 1932 AN: 3022

European-Finnish (FIN) AF: 0.627 AC: 13059 AN: 20822

Middle Eastern (MID) AF: 0.532 AC: 688 AN: 1294

European-Non Finnish (NFE) AF: 0.587 AC: 92787 AN: 158016

Other (OTH) AF: 0.568 AC: 9296 AN: 16368

GnomAD4 genome AF: 0.532 AC: 80952 AN: 152046 Hom.: 22666 Cov.: 32 AF XY: 0.539 AC XY: 40077 AN XY: 74328

African (AFR) AF: 0.352 AC: 14573 AN: 41438

American (AMR) AF: 0.553 AC: 8455 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 1729 AN: 3472

East Asian (EAS) AF: 0.794 AC: 4109 AN: 5178

South Asian (SAS) AF: 0.638 AC: 3075 AN: 4822

European-Finnish (FIN) AF: 0.636 AC: 6723 AN: 10570

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40501 AN: 67972

Other (OTH) AF: 0.530 AC: 1120 AN: 2112

Alfa AF: 0.569 Hom.: 72543

Bravo AF: 0.518

Asia WGS AF: 0.605 AC: 2102 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		-0.24
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: rs10766212; hg19: chr11-2633152;