chr11-2610716-CTTTTTTTTTTT-C

Variant names:

• chr11-2610716-CTTTTTTTTTTT-C
• rs1167505141
• NM_000218.3:c.1393+21881_1393+21891delTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000218.3(KCNQ1):​c.1393+21881_1393+21891delTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0648 in 227,520 control chromosomes in the GnomAD database, including 10 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (9 hom., cov: 0)
  • Exomes 𝑓: 0.086 (1 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.514

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 -10 ACMG points.

• BP6: Variant 11-2610716-CTTTTTTTTTTT-C is Benign according to our data. Variant chr11-2610716-CTTTTTTTTTTT-C is described in ClinVar as [Benign]. Clinvar id is 2582883.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1393+21881_1393+21891delTTTTTTTTTTT		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+21881_1393+21891delTTTTTTTTTTT		intron_variant	Intron 10 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 372 AN: 59576 Hom.: 9 Cov.: 0

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00515

Gnomad ASJ AF: 0.00775

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00280

Gnomad FIN AF: 0.0305

Gnomad MID AF: 0.0189

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.00616

GnomAD4 exome AF: 0.0856 AC: 14370 AN: 167944 Hom.: 1 AF XY: 0.0854 AC XY: 7312 AN XY: 85600

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.0884

Gnomad4 EAS exome AF: 0.0732

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.0538

Gnomad4 NFE exome AF: 0.0861

Gnomad4 OTH exome AF: 0.0924

GnomAD4 genome AF: 0.00624 AC: 372 AN: 59576 Hom.: 9 Cov.: 0 AF XY: 0.00637 AC XY: 171 AN XY: 26844

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.00515

Gnomad4 ASJ AF: 0.00775

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00283

Gnomad4 FIN AF: 0.0305

Gnomad4 NFE AF: 0.00298

Gnomad4 OTH AF: 0.00608

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ1OT1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1167505141; hg19: chr11-2631946;