chr11-2684113-A-T

Variant names:

• chr11-2684113-A-T
• rs231356
• NM_000218.3:c.1514+22032A>T

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+22032A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 398,404 control chromosomes in the GnomAD database, including 27,240 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 0.32 (8644 hom., cov: 33)
  • Exomes 𝑓: 0.35 (18596 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217
• Publications: 36 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1514+22032A>T		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+22032A>T		intron_variant	Intron 11 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48276 AN: 151978 Hom.: 8630 Cov.: 33

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.309

GnomAD4 exome AF: 0.352 AC: 86615 AN: 246308 Hom.: 18596 Cov.: 0 AF XY: 0.351 AC XY: 43805 AN XY: 124798

African (AFR) AF: 0.246 AC: 1765 AN: 7180

American (AMR) AF: 0.412 AC: 3063 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 2134 AN: 9240

East Asian (EAS) AF: 0.838 AC: 19178 AN: 22894

South Asian (SAS) AF: 0.495 AC: 1501 AN: 3032

European-Finnish (FIN) AF: 0.346 AC: 7215 AN: 20824

Middle Eastern (MID) AF: 0.243 AC: 314 AN: 1294

European-Non Finnish (NFE) AF: 0.292 AC: 46081 AN: 158040

Other (OTH) AF: 0.328 AC: 5364 AN: 16370

GnomAD4 genome AF: 0.318 AC: 48312 AN: 152096 Hom.: 8644 Cov.: 33 AF XY: 0.328 AC XY: 24376 AN XY: 74334

African (AFR) AF: 0.253 AC: 10479 AN: 41486

American (AMR) AF: 0.379 AC: 5791 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 843 AN: 3472

East Asian (EAS) AF: 0.807 AC: 4171 AN: 5168

South Asian (SAS) AF: 0.484 AC: 2332 AN: 4820

European-Finnish (FIN) AF: 0.353 AC: 3733 AN: 10574

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20131 AN: 67968

Other (OTH) AF: 0.314 AC: 665 AN: 2116

Alfa AF: 0.167 Hom.: 342

Bravo AF: 0.314

Asia WGS AF: 0.574 AC: 1996 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	1.5
DANN	Benign	0.54
PhyloP100		-0.22
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: rs231356; hg19: chr11-2705343;