11-2683945-A-G

Variant names:

• chr11-2683945-A-G
• rs231357
• NM_000218.3:c.1514+21864A>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.1514+21864A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 397,796 control chromosomes in the GnomAD database, including 73,480 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 0.61 (30115 hom., cov: 30)
  • Exomes 𝑓: 0.57 (43365 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.91
• Publications: 20 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 = 0.966 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1514+21864A>G		intron	N/A	NP_000209.2
	KCNQ1OT1	NR_002728.4	MANE Select	n.16050T>C		non_coding_transcript_exon	Exon 1 of 1
	KCNQ1	NM_001406836.1		c.1418+21864A>G		intron	N/A	NP_001393765.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1514+21864A>G		intron	N/A	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1133+21864A>G		intron	N/A	ENSP00000334497.5	P51787-2
	KCNQ1OT1	ENST00000597346.1	TSL:6 MANE Select	n.16050T>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.614 AC: 92957 AN: 151378 Hom.: 30061 Cov.: 30

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.617

Gnomad MID AF: 0.539

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.603

GnomAD4 exome AF: 0.571 AC: 140731 AN: 246306 Hom.: 43365 Cov.: 0 AF XY: 0.569 AC XY: 71060 AN XY: 124802

African (AFR) AF: 0.734 AC: 5270 AN: 7180

American (AMR) AF: 0.697 AC: 5180 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 5528 AN: 9240

East Asian (EAS) AF: 0.998 AC: 22843 AN: 22892

South Asian (SAS) AF: 0.848 AC: 2572 AN: 3032

European-Finnish (FIN) AF: 0.595 AC: 12382 AN: 20824

Middle Eastern (MID) AF: 0.567 AC: 734 AN: 1294

European-Non Finnish (NFE) AF: 0.484 AC: 76543 AN: 158038

Other (OTH) AF: 0.591 AC: 9679 AN: 16372

GnomAD4 genome AF: 0.614 AC: 93074 AN: 151490 Hom.: 30115 Cov.: 30 AF XY: 0.628 AC XY: 46446 AN XY: 73992

African (AFR) AF: 0.750 AC: 30996 AN: 41302

American (AMR) AF: 0.653 AC: 9951 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2106 AN: 3472

East Asian (EAS) AF: 0.989 AC: 5124 AN: 5182

South Asian (SAS) AF: 0.846 AC: 4069 AN: 4812

European-Finnish (FIN) AF: 0.617 AC: 6366 AN: 10312

Middle Eastern (MID) AF: 0.539 AC: 153 AN: 284

European-Non Finnish (NFE) AF: 0.482 AC: 32708 AN: 67860

Other (OTH) AF: 0.608 AC: 1281 AN: 2106

Alfa AF: 0.537 Hom.: 9026

Bravo AF: 0.620

Asia WGS AF: 0.888 AC: 3085 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.37
DANN	Benign	0.52
PhyloP100		-1.9
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: rs231357; hg19: chr11-2705175;