rs760419

Variant names:

• chr11-2662127-A-G
• rs760419
• NM_000218.3:c.1514+46A>G

Variant summary

Our verdict is Benign. The variant received -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 (★★). The gene KCNQ1 is included in the ClinGen Criteria Specification Registry.

• 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
• Publications: 31 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

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -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 VariationId is 1272027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 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+46A>G		intron	N/A	NP_000209.2
	KCNQ1OT1	NR_002728.4	MANE Select	n.37868T>C		non_coding_transcript_exon	Exon 1 of 1
	KCNQ1	NM_001406836.1		c.1418+46A>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+46A>G		intron	N/A	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1133+46A>G		intron	N/A	ENSP00000334497.5	P51787-2
	KCNQ1OT1	ENST00000597346.1	TSL:6 MANE Select	n.37868T>C		non_coding_transcript_exon	Exon 1 of 1

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

GnomAD2 exomes AF: 0.437 AC: 109359 AN: 250252 AF XY: 0.432

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 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

African (AFR) AF: 0.817 AC: 27342 AN: 33446

American (AMR) AF: 0.318 AC: 14211 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 9309 AN: 26104

East Asian (EAS) AF: 0.387 AC: 15350 AN: 39678

South Asian (SAS) AF: 0.379 AC: 32700 AN: 86190

European-Finnish (FIN) AF: 0.486 AC: 25773 AN: 53064

Middle Eastern (MID) AF: 0.309 AC: 1759 AN: 5686

European-Non Finnish (NFE) AF: 0.468 AC: 519812 AN: 1110824

Other (OTH) AF: 0.458 AC: 27650 AN: 60326

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

African (AFR) AF: 0.803 AC: 33309 AN: 41500

American (AMR) AF: 0.392 AC: 6000 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1215 AN: 3462

East Asian (EAS) AF: 0.342 AC: 1759 AN: 5144

South Asian (SAS) AF: 0.392 AC: 1889 AN: 4822

European-Finnish (FIN) AF: 0.484 AC: 5114 AN: 10570

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.462 AC: 31413 AN: 67964

Other (OTH) AF: 0.510 AC: 1079 AN: 2114

Alfa AF: 0.465 Hom.: 34735

Bravo AF: 0.544

Asia WGS AF: 0.458 AC: 1592 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.4
DANN	Benign	0.25
PhyloP100		0.017
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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