11-2661922-T-G

Variant names:

• chr11-2661922-T-G
• rs739502
• NM_000218.3:c.1394-39T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000218.3(KCNQ1):​c.1394-39T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,612,768 control chromosomes in the GnomAD database, including 13,121 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 0.18 (3776 hom., cov: 32)
  • Exomes 𝑓: 0.10 (9345 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.273
• Publications: 11 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=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1394-39T>G		intron_variant	Intron 10 of 15	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1394-39T>G		intron_variant	Intron 10 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27052 AN: 151926 Hom.: 3752 Cov.: 32

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0537

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0916

Gnomad OTH AF: 0.165

GnomAD2 exomes AF: 0.116 AC: 28924 AN: 249838 AF XY: 0.113

Gnomad AFR exome AF: 0.398

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.0546

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.0911

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.0997 AC: 145679 AN: 1460724 Hom.: 9345 Cov.: 33 AF XY: 0.101 AC XY: 73088 AN XY: 726688

African (AFR) AF: 0.403 AC: 13495 AN: 33448

American (AMR) AF: 0.0793 AC: 3545 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2710 AN: 26130

East Asian (EAS) AF: 0.0514 AC: 2041 AN: 39684

South Asian (SAS) AF: 0.147 AC: 12657 AN: 86232

European-Finnish (FIN) AF: 0.111 AC: 5877 AN: 52842

Middle Eastern (MID) AF: 0.0888 AC: 512 AN: 5764

European-Non Finnish (NFE) AF: 0.0884 AC: 98227 AN: 1111554

Other (OTH) AF: 0.110 AC: 6615 AN: 60362

GnomAD4 genome AF: 0.178 AC: 27122 AN: 152044 Hom.: 3776 Cov.: 32 AF XY: 0.175 AC XY: 13033 AN XY: 74332

African (AFR) AF: 0.392 AC: 16265 AN: 41442

American (AMR) AF: 0.114 AC: 1751 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3472

East Asian (EAS) AF: 0.0538 AC: 278 AN: 5166

South Asian (SAS) AF: 0.147 AC: 708 AN: 4810

European-Finnish (FIN) AF: 0.100 AC: 1060 AN: 10580

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0916 AC: 6223 AN: 67964

Other (OTH) AF: 0.164 AC: 346 AN: 2110

Alfa AF: 0.0964 Hom.: 303

Bravo AF: 0.187

Asia WGS AF: 0.137 AC: 477 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.11
DANN	Benign	0.83
PhyloP100		0.27
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: rs739502; hg19: chr11-2683152; COSMIC: COSV108030964;