rs760419

Positions:

• chr11-2662127-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000218.3(KCNQ1):​c.1514+46A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,612,088 control chromosomes in the GnomAD database, including 184,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (24456 hom., cov: 33)
  • Exomes 𝑓: 0.46 (159982 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0170

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-2662127-A-G is Benign according to our data. Variant chr11-2662127-A-G is described in ClinVar as [Benign]. Clinvar id is 1272027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2662127-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1514+46A>G		intron_variant		ENST00000155840.12	NP_000209.2
KCNQ1OT1	NR_002728.3	n.37872T>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1514+46A>G		intron_variant		1	NM_000218.3	ENSP00000155840	P1
KCNQ1OT1	ENST00000710656.1	n.376-21012T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82249 AN: 151954 Hom.: 24414 Cov.: 33

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.509

GnomAD3 exomes AF: 0.437 AC: 109359 AN: 250252 Hom.: 25902 AF XY: 0.432 AC XY: 58353 AN XY: 135220

Gnomad AFR exome AF: 0.808

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.311

Gnomad SAS exome AF: 0.386

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.457

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.462 AC: 673906 AN: 1460016 Hom.: 159982 Cov.: 39 AF XY: 0.457 AC XY: 332039 AN XY: 726180

Gnomad4 AFR exome AF: 0.817

Gnomad4 AMR exome AF: 0.318

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.387

Gnomad4 SAS exome AF: 0.379

Gnomad4 FIN exome AF: 0.486

Gnomad4 NFE exome AF: 0.468

Gnomad4 OTH exome AF: 0.458

GnomAD4 genome AF: 0.541 AC: 82344 AN: 152072 Hom.: 24456 Cov.: 33 AF XY: 0.535 AC XY: 39733 AN XY: 74324

Gnomad4 AFR AF: 0.803

Gnomad4 AMR AF: 0.392

Gnomad4 ASJ AF: 0.351

Gnomad4 EAS AF: 0.342

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.484

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.510

Alfa AF: 0.455 Hom.: 24361

Bravo AF: 0.544

Asia WGS AF: 0.458 AC: 1592 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.4
DANN	Benign	0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs760419; hg19: chr11-2683357; COSMIC: COSV50099903;