rs3782064

Positions:

• chr11-2699927-G-A

Variant summary

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

The NM_000218.3(KCNQ1):​c.1514+37846G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 398,412 control chromosomes in the GnomAD database, including 193 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 0.011 (50 hom., cov: 33)
  • Exomes 𝑓: 0.016 (143 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.63

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=-0.59).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1514+37846G>A		intron_variant		ENST00000155840.12	NP_000209.2
KCNQ1OT1	NR_002728.3	n.72C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1514+37846G>A		intron_variant		1	NM_000218.3	ENSP00000155840	P1
KCNQ1OT1	ENST00000710656.1	n.77C>T		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1710 AN: 152118 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0892

Gnomad SAS AF: 0.00788

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0162 AC: 3993 AN: 246176 Hom.: 143 Cov.: 0 AF XY: 0.0153 AC XY: 1904 AN XY: 124804

Gnomad4 AFR exome AF: 0.000977

Gnomad4 AMR exome AF: 0.0548

Gnomad4 ASJ exome AF: 0.00510

Gnomad4 EAS exome AF: 0.0958

Gnomad4 SAS exome AF: 0.00361

Gnomad4 FIN exome AF: 0.0417

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0112 AC: 1712 AN: 152236 Hom.: 50 Cov.: 33 AF XY: 0.0135 AC XY: 1007 AN XY: 74436

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.0372

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.0893

Gnomad4 SAS AF: 0.00809

Gnomad4 FIN AF: 0.0411

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00651 Hom.: 1

Bravo AF: 0.0122

Asia WGS AF: 0.0490 AC: 168 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.2
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3782064; hg19: chr11-2721157;