11-2689592-T-C

Position:

• chr11-2689592-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000218.3(KCNQ1):​c.1514+27511T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 398,460 control chromosomes in the GnomAD database, including 73,861 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 (31138 hom., cov: 33)
  • Exomes 𝑓: 0.57 (42723 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.42

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-2689592-T-C is Benign according to our data. Variant chr11-2689592-T-C is described in ClinVar as [Benign]. Clinvar id is 3060442.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1514+27511T>C		intron_variant		ENST00000155840.12
KCNQ1OT1	NR_002728.3	n.10407A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1514+27511T>C		intron_variant		1	NM_000218.3	P1
KCNQ1OT1	ENST00000710656.1	n.375+9736A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94917 AN: 151998 Hom.: 31086 Cov.: 33

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.601

GnomAD4 exome AF: 0.574 AC: 141508 AN: 246344 Hom.: 42723 Cov.: 0 AF XY: 0.573 AC XY: 71561 AN XY: 124824

Gnomad4 AFR exome AF: 0.776

Gnomad4 AMR exome AF: 0.661

Gnomad4 ASJ exome AF: 0.609

Gnomad4 EAS exome AF: 0.899

Gnomad4 SAS exome AF: 0.848

Gnomad4 FIN exome AF: 0.576

Gnomad4 NFE exome AF: 0.504

Gnomad4 OTH exome AF: 0.596

GnomAD4 genome AF: 0.625 AC: 95030 AN: 152116 Hom.: 31138 Cov.: 33 AF XY: 0.634 AC XY: 47119 AN XY: 74346

Gnomad4 AFR AF: 0.780

Gnomad4 AMR AF: 0.633

Gnomad4 ASJ AF: 0.612

Gnomad4 EAS AF: 0.900

Gnomad4 SAS AF: 0.840

Gnomad4 FIN AF: 0.586

Gnomad4 NFE AF: 0.503

Gnomad4 OTH AF: 0.605

Alfa AF: 0.568 Hom.: 4328

Bravo AF: 0.634

Asia WGS AF: 0.840 AC: 2921 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KCNQ1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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	-0.92
CADD	Benign	0.51
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs231352; hg19: chr11-2710822;