11-2609494-A-G

Variant names:

• chr11-2609494-A-G
• rs566148304
• NM_000218.3:c.1393+20640A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000218.3(KCNQ1):​c.1393+20640A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 398,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.673

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 11-2609494-A-G is Benign according to our data. Variant chr11-2609494-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3771728.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1393+20640A>G		intron_variant	Intron 10 of 15	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1393+20640A>G		intron_variant	Intron 10 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.000435 AC: 107 AN: 246074 Hom.: 0 Cov.: 0 AF XY: 0.000369 AC XY: 46 AN XY: 124694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000404

Gnomad4 ASJ exome AF: 0.000217

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000144

Gnomad4 NFE exome AF: 0.000595

Gnomad4 OTH exome AF: 0.000245

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74324

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000423

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ1OT1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.6
DANN	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs566148304; hg19: chr11-2630724;