11-2631427-T-G

Variant names:

• chr11-2631427-T-G
• rs10832417
• NM_000218.3:c.1394-30534T>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.1394-30534T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 390,536 control chromosomes in the GnomAD database, including 24,240 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 (8648 hom., cov: 32)
  • Exomes 𝑓: 0.35 (15592 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.77
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.695 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1394-30534T>G		intron	N/A	NP_000209.2
	KCNQ1OT1	NR_002728.4	MANE Select	n.68568A>C		non_coding_transcript_exon	Exon 1 of 1
	KCNQ1	NM_001406836.1		c.1298-30534T>G		intron	N/A	NP_001393765.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1394-30534T>G		intron	N/A	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.1013-30534T>G		intron	N/A	ENSP00000334497.5
	KCNQ1OT1	ENST00000597346.1	TSL:6 MANE Select	n.68568A>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 48576 AN: 149904 Hom.: 8638 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.715

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.276

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.327

GnomAD4 exome AF: 0.346 AC: 83218 AN: 240524 Hom.: 15592 Cov.: 0 AF XY: 0.345 AC XY: 42073 AN XY: 121780

African (AFR) AF: 0.274 AC: 1905 AN: 6958

American (AMR) AF: 0.488 AC: 3559 AN: 7290

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 3102 AN: 9032

East Asian (EAS) AF: 0.627 AC: 14222 AN: 22700

South Asian (SAS) AF: 0.497 AC: 1471 AN: 2962

European-Finnish (FIN) AF: 0.391 AC: 7985 AN: 20442

Middle Eastern (MID) AF: 0.315 AC: 398 AN: 1264

European-Non Finnish (NFE) AF: 0.292 AC: 44928 AN: 153852

Other (OTH) AF: 0.352 AC: 5648 AN: 16024

GnomAD4 genome AF: 0.324 AC: 48617 AN: 150012 Hom.: 8648 Cov.: 32 AF XY: 0.337 AC XY: 24690 AN XY: 73254

African (AFR) AF: 0.254 AC: 10361 AN: 40830

American (AMR) AF: 0.427 AC: 6457 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1196 AN: 3390

East Asian (EAS) AF: 0.715 AC: 3677 AN: 5146

South Asian (SAS) AF: 0.508 AC: 2430 AN: 4788

European-Finnish (FIN) AF: 0.399 AC: 4105 AN: 10276

Middle Eastern (MID) AF: 0.266 AC: 77 AN: 290

European-Non Finnish (NFE) AF: 0.289 AC: 19421 AN: 67176

Other (OTH) AF: 0.332 AC: 689 AN: 2076

Alfa AF: 0.289 Hom.: 4710

Bravo AF: 0.323

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.1
DANN	Benign	0.38
PhyloP100		-1.8
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: rs10832417; hg19: chr11-2652657;