11-2683945-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000218.3(KCNQ1):c.1514+21864A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 397,796 control chromosomes in the GnomAD database, including 73,480 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 0.61 (30115 hom., cov: 30)
  • Exomes 𝑓: 0.57 (43365 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.91

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1514+21864A>G		intron_variant		ENST00000155840.12
KCNQ1OT1	NR_002728.3	n.16054T>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1514+21864A>G		intron_variant		1	NM_000218.3	P1
KCNQ1OT1	ENST00000710656.1	n.375+15383T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.614 AC: 92957 AN: 151378 Hom.: 30061 Cov.: 30

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.617

Gnomad MID AF: 0.539

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.603

GnomAD4 exome AF: 0.571 AC: 140731 AN: 246306 Hom.: 43365 Cov.: 0 AF XY: 0.569 AC XY: 71060 AN XY: 124802

Gnomad4 AFR exome AF: 0.734

Gnomad4 AMR exome AF: 0.697

Gnomad4 ASJ exome AF: 0.598

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.848

Gnomad4 FIN exome AF: 0.595

Gnomad4 NFE exome AF: 0.484

Gnomad4 OTH exome AF: 0.591

GnomAD4 genome AF: 0.614 AC: 93074 AN: 151490 Hom.: 30115 Cov.: 30 AF XY: 0.628 AC XY: 46446 AN XY: 73992

Gnomad4 AFR AF: 0.750

Gnomad4 AMR AF: 0.653

Gnomad4 ASJ AF: 0.607

Gnomad4 EAS AF: 0.989

Gnomad4 SAS AF: 0.846

Gnomad4 FIN AF: 0.617

Gnomad4 NFE AF: 0.482

Gnomad4 OTH AF: 0.608

Alfa AF: 0.540 Hom.: 5755

Bravo AF: 0.620

Asia WGS AF: 0.888 AC: 3085 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.37
Dann	Benign	0.52

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: rs231357; hg19: chr11-2705175;