11-2685097-G-C

Variant names:

• chr11-2685097-G-C
• rs231355
• NM_000218.3:c.1514+23016G>C

Variant summary

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

The NM_000218.3(KCNQ1):​c.1514+23016G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 398,524 control chromosomes in the GnomAD database, including 77,824 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 0.64 (32676 hom., cov: 33)
  • Exomes 𝑓: 0.58 (45148 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.02
• 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]

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1514+23016G>C		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+23016G>C		intron_variant	Intron 11 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96900 AN: 152074 Hom.: 32615 Cov.: 33

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.847

Gnomad FIN AF: 0.624

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.612

GnomAD4 exome AF: 0.584 AC: 143979 AN: 246332 Hom.: 45148 Cov.: 0 AF XY: 0.582 AC XY: 72697 AN XY: 124826

African (AFR) AF: 0.790 AC: 5671 AN: 7180

American (AMR) AF: 0.710 AC: 5276 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 5461 AN: 9240

East Asian (EAS) AF: 0.995 AC: 22788 AN: 22896

South Asian (SAS) AF: 0.853 AC: 2586 AN: 3032

European-Finnish (FIN) AF: 0.615 AC: 12798 AN: 20824

Middle Eastern (MID) AF: 0.567 AC: 734 AN: 1294

European-Non Finnish (NFE) AF: 0.498 AC: 78734 AN: 158062

Other (OTH) AF: 0.607 AC: 9931 AN: 16370

GnomAD4 genome AF: 0.638 AC: 97026 AN: 152192 Hom.: 32676 Cov.: 33 AF XY: 0.649 AC XY: 48269 AN XY: 74404

African (AFR) AF: 0.802 AC: 33333 AN: 41540

American (AMR) AF: 0.667 AC: 10204 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 2073 AN: 3472

East Asian (EAS) AF: 0.988 AC: 5100 AN: 5164

South Asian (SAS) AF: 0.848 AC: 4091 AN: 4826

European-Finnish (FIN) AF: 0.624 AC: 6619 AN: 10608

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33821 AN: 67976

Other (OTH) AF: 0.617 AC: 1304 AN: 2114

Alfa AF: 0.569 Hom.: 2813

Bravo AF: 0.646

Asia WGS AF: 0.889 AC: 3091 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.18
DANN	Benign	0.42
PhyloP100		-5.0
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: rs231355; hg19: chr11-2706327;