11-2696063-T-C

Variant names:

• chr11-2696063-T-C
• rs462402
• NM_000218.3:c.1514+33982T>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+33982T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 398,438 control chromosomes in the GnomAD database, including 83,319 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 0.67 (35851 hom., cov: 33)
  • Exomes 𝑓: 0.60 (47468 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 16 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=-0.92).
• 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+33982T>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+33982T>C		intron_variant	Intron 11 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.665 AC: 101149 AN: 152028 Hom.: 35791 Cov.: 33

Gnomad AFR AF: 0.867

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.852

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.634

GnomAD4 exome AF: 0.601 AC: 148100 AN: 246292 Hom.: 47468 Cov.: 0 AF XY: 0.599 AC XY: 74703 AN XY: 124790

African (AFR) AF: 0.859 AC: 6171 AN: 7180

American (AMR) AF: 0.728 AC: 5412 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 5602 AN: 9238

East Asian (EAS) AF: 0.995 AC: 22783 AN: 22890

South Asian (SAS) AF: 0.854 AC: 2589 AN: 3030

European-Finnish (FIN) AF: 0.625 AC: 13017 AN: 20824

Middle Eastern (MID) AF: 0.600 AC: 776 AN: 1294

European-Non Finnish (NFE) AF: 0.516 AC: 81511 AN: 158032

Other (OTH) AF: 0.625 AC: 10239 AN: 16370

GnomAD4 genome AF: 0.666 AC: 101271 AN: 152146 Hom.: 35851 Cov.: 33 AF XY: 0.675 AC XY: 50221 AN XY: 74358

African (AFR) AF: 0.867 AC: 36002 AN: 41530

American (AMR) AF: 0.680 AC: 10395 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2102 AN: 3472

East Asian (EAS) AF: 0.988 AC: 5121 AN: 5184

South Asian (SAS) AF: 0.851 AC: 4112 AN: 4830

European-Finnish (FIN) AF: 0.636 AC: 6718 AN: 10562

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.515 AC: 34979 AN: 67960

Other (OTH) AF: 0.639 AC: 1350 AN: 2112

Alfa AF: 0.555 Hom.: 11178

Bravo AF: 0.678

Asia WGS AF: 0.895 AC: 3112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.089
DANN	Benign	0.70
PhyloP100		-1.6
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: rs462402; hg19: chr11-2717293;