11-2681283-C-T

Variant names:

• chr11-2681283-C-T
• rs231358
• NM_000218.3:c.1514+19202C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000218.3(KCNQ1):​c.1514+19202C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 398,146 control chromosomes in the GnomAD database, including 74,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.62 (31126 hom., cov: 30)
  • Exomes 𝑓: 0.57 (43295 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.813
• Publications: 18 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]

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]

KCNQ1OT1 Gene-Disease associations (from GenCC):

• Beckwith-Wiedemann syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-2681283-C-T is Benign according to our data. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-2681283-C-T is described in CliVar as Benign. Clinvar id is 3060959.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1514+19202C>T		intron_variant	Intron 11 of 15	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1514+19202C>T		intron_variant	Intron 11 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94226 AN: 151708 Hom.: 31071 Cov.: 30

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.599

GnomAD4 exome AF: 0.570 AC: 140345 AN: 246320 Hom.: 43295 Cov.: 0 AF XY: 0.568 AC XY: 70848 AN XY: 124810

African (AFR) AF: 0.772 AC: 5540 AN: 7180

American (AMR) AF: 0.700 AC: 5206 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 5336 AN: 9242

East Asian (EAS) AF: 0.995 AC: 22785 AN: 22894

South Asian (SAS) AF: 0.843 AC: 2555 AN: 3032

European-Finnish (FIN) AF: 0.607 AC: 12642 AN: 20826

Middle Eastern (MID) AF: 0.569 AC: 736 AN: 1294

European-Non Finnish (NFE) AF: 0.480 AC: 75908 AN: 158048

Other (OTH) AF: 0.589 AC: 9637 AN: 16370

GnomAD4 genome AF: 0.621 AC: 94347 AN: 151826 Hom.: 31126 Cov.: 30 AF XY: 0.634 AC XY: 46997 AN XY: 74180

African (AFR) AF: 0.786 AC: 32560 AN: 41414

American (AMR) AF: 0.653 AC: 9970 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 1999 AN: 3464

East Asian (EAS) AF: 0.987 AC: 5054 AN: 5120

South Asian (SAS) AF: 0.841 AC: 4047 AN: 4814

European-Finnish (FIN) AF: 0.619 AC: 6517 AN: 10522

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.478 AC: 32462 AN: 67908

Other (OTH) AF: 0.604 AC: 1276 AN: 2112

Alfa AF: 0.529 Hom.: 76568

Bravo AF: 0.631

Asia WGS AF: 0.877 AC: 3049 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KCNQ1-related disorder Benign:1

Sep 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.63
DANN	Benign	0.65
PhyloP100		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs231358; hg19: chr11-2702513;