11-2673376-C-A

Variant names:

• chr11-2673376-C-A
• rs231359
• NM_000218.3:c.1514+11295C>A

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+11295C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 398,476 control chromosomes in the GnomAD database, including 29,403 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 0.36 (10703 hom., cov: 33)
  • Exomes 𝑓: 0.35 (18700 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.833
• Publications: 37 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1514+11295C>A		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+11295C>A		intron_variant	Intron 11 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54453 AN: 152032 Hom.: 10688 Cov.: 33

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.353 AC: 87034 AN: 246326 Hom.: 18700 Cov.: 0 AF XY: 0.353 AC XY: 43999 AN XY: 124816

African (AFR) AF: 0.394 AC: 2829 AN: 7180

American (AMR) AF: 0.421 AC: 3130 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 2130 AN: 9240

East Asian (EAS) AF: 0.837 AC: 19163 AN: 22896

South Asian (SAS) AF: 0.520 AC: 1575 AN: 3030

European-Finnish (FIN) AF: 0.343 AC: 7140 AN: 20830

Middle Eastern (MID) AF: 0.234 AC: 303 AN: 1294

European-Non Finnish (NFE) AF: 0.286 AC: 45207 AN: 158052

Other (OTH) AF: 0.339 AC: 5557 AN: 16370

GnomAD4 genome AF: 0.358 AC: 54498 AN: 152150 Hom.: 10703 Cov.: 33 AF XY: 0.368 AC XY: 27348 AN XY: 74392

African (AFR) AF: 0.402 AC: 16691 AN: 41492

American (AMR) AF: 0.394 AC: 6036 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 838 AN: 3470

East Asian (EAS) AF: 0.809 AC: 4185 AN: 5174

South Asian (SAS) AF: 0.512 AC: 2474 AN: 4832

European-Finnish (FIN) AF: 0.348 AC: 3685 AN: 10584

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19726 AN: 67974

Other (OTH) AF: 0.336 AC: 709 AN: 2110

Alfa AF: 0.310 Hom.: 24585

Bravo AF: 0.362

Asia WGS AF: 0.587 AC: 2040 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.13
DANN	Benign	0.79
PhyloP100		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs231359; hg19: chr11-2694606;