rs231361

Positions:

• chr11-2670270-G-A
• chr11-2670270-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1514+8189G>A		intron_variant		ENST00000155840.12
KCNQ1OT1	NR_002728.3	n.29729C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1514+8189G>A		intron_variant		1	NM_000218.3	P1
KCNQ1OT1	ENST00000710656.1	n.375+29058C>T		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.334

Gnomad4 AMR exome AF: 0.396

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.835

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.296

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.303

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

Gnomad4 AFR AF: 0.342

Gnomad4 AMR AF: 0.370

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.805

Gnomad4 SAS AF: 0.462

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.299

Alfa AF: 0.259 Hom.: 7626

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs231361; hg19: chr11-2691500;