rs231361

Variant names:

• chr11-2670270-G-A
• rs231361
• NM_000218.3:c.1514+8189G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2670270-G-A
• chr11-2670270-G-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.1514+8189G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 398,378 control chromosomes in the GnomAD database, including 24,592 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 0.31 (8472 hom., cov: 32)
  • Exomes 𝑓: 0.32 (16120 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.146
• Publications: 68 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1514+8189G>A		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+8189G>A		intron_variant	Intron 11 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47630 AN: 151942 Hom.: 8457 Cov.: 32

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.292

GnomAD4 exome AF: 0.316 AC: 77946 AN: 246318 Hom.: 16120 Cov.: 0 AF XY: 0.314 AC XY: 39219 AN XY: 124816

African (AFR) AF: 0.334 AC: 2398 AN: 7180

American (AMR) AF: 0.396 AC: 2947 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 1787 AN: 9240

East Asian (EAS) AF: 0.835 AC: 19118 AN: 22894

South Asian (SAS) AF: 0.476 AC: 1437 AN: 3022

European-Finnish (FIN) AF: 0.296 AC: 6155 AN: 20822

Middle Eastern (MID) AF: 0.211 AC: 273 AN: 1294

European-Non Finnish (NFE) AF: 0.246 AC: 38871 AN: 158062

Other (OTH) AF: 0.303 AC: 4960 AN: 16370

GnomAD4 genome AF: 0.314 AC: 47673 AN: 152060 Hom.: 8472 Cov.: 32 AF XY: 0.324 AC XY: 24107 AN XY: 74348

African (AFR) AF: 0.342 AC: 14159 AN: 41450

American (AMR) AF: 0.370 AC: 5657 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 712 AN: 3470

East Asian (EAS) AF: 0.805 AC: 4164 AN: 5174

South Asian (SAS) AF: 0.462 AC: 2232 AN: 4826

European-Finnish (FIN) AF: 0.307 AC: 3243 AN: 10576

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16760 AN: 67962

Other (OTH) AF: 0.299 AC: 630 AN: 2108

Alfa AF: 0.267 Hom.: 11493

Bravo AF: 0.318

Asia WGS AF: 0.554 AC: 1927 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.49
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs231361; hg19: chr11-2691500;