11-2610716-CTTTTTTTTT-C

Position:

• chr11-2610716-CTTTTTTTTT-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000155840.12(KCNQ1):​c.1393+21883_1393+21891del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 230,054 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0036 (0 hom.)
• Consequence: KCNQ1 ENST00000155840.12 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-CTTTTTTTTT-C is Benign according to our data. Variant chr11-2610716-CTTTTTTTTT-C is described in ClinVar as [Benign]. Clinvar id is 2641365.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00698 (416/59576) while in subpopulation EAS AF= 0.0391 (49/1254). AF 95% confidence interval is 0.0304. There are 2 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1393+21883_1393+21891del		intron_variant		ENST00000155840.12	NP_000209.2
KCNQ1OT1	NR_002728.3	n.89274_89282del		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1393+21883_1393+21891del		intron_variant		1	NM_000218.3	ENSP00000155840	P1
KCNQ1OT1	ENST00000710656.1	n.452-13190_452-13182del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 415 AN: 59576 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00332

Gnomad EAS AF: 0.0388

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00211

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00596

Gnomad OTH AF: 0.0111

GnomAD4 exome AF: 0.00364 AC: 620 AN: 170478 Hom.: 0 AF XY: 0.00385 AC XY: 335 AN XY: 86942

Gnomad4 AFR exome AF: 0.00471

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00381

Gnomad4 EAS exome AF: 0.0131

Gnomad4 SAS exome AF: 0.00373

Gnomad4 FIN exome AF: 0.00201

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00256

GnomAD4 genome AF: 0.00698 AC: 416 AN: 59576 Hom.: 2 Cov.: 0 AF XY: 0.00693 AC XY: 186 AN XY: 26846

Gnomad4 AFR AF: 0.00707

Gnomad4 AMR AF: 0.00622

Gnomad4 ASJ AF: 0.00332

Gnomad4 EAS AF: 0.0391

Gnomad4 SAS AF: 0.0113

Gnomad4 FIN AF: 0.00211

Gnomad4 NFE AF: 0.00596

Gnomad4 OTH AF: 0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

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;