11-2612485-G-C

Position:

• chr11-2612485-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000155840.12(KCNQ1):​c.1393+23631G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 398,354 control chromosomes in the GnomAD database, including 71,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.61 (29011 hom., cov: 32)
  • Exomes 𝑓: 0.58 (42492 hom.)
• Consequence: KCNQ1 ENST00000155840.12 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.920

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 11-2612485-G-C is Benign according to our data. Variant chr11-2612485-G-C is described in ClinVar as [Benign]. Clinvar id is 3059785.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1393+23631G>C		intron_variant		ENST00000155840.12	NP_000209.2
KCNQ1OT1	NR_002728.3	n.87514C>G		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+23631G>C		intron_variant		1	NM_000218.3	ENSP00000155840	P1
KCNQ1OT1	ENST00000710656.1	n.452-14950C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92882 AN: 151942 Hom.: 28972 Cov.: 32

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.585

GnomAD4 exome AF: 0.581 AC: 142985 AN: 246294 Hom.: 42492 Cov.: 0 AF XY: 0.578 AC XY: 72102 AN XY: 124798

Gnomad4 AFR exome AF: 0.681

Gnomad4 AMR exome AF: 0.643

Gnomad4 ASJ exome AF: 0.506

Gnomad4 EAS exome AF: 0.793

Gnomad4 SAS exome AF: 0.692

Gnomad4 FIN exome AF: 0.638

Gnomad4 NFE exome AF: 0.537

Gnomad4 OTH exome AF: 0.584

GnomAD4 genome AF: 0.611 AC: 92971 AN: 152060 Hom.: 29011 Cov.: 32 AF XY: 0.619 AC XY: 46030 AN XY: 74344

Gnomad4 AFR AF: 0.685

Gnomad4 AMR AF: 0.637

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.833

Gnomad4 SAS AF: 0.682

Gnomad4 FIN AF: 0.650

Gnomad4 NFE AF: 0.541

Gnomad4 OTH AF: 0.580

Alfa AF: 0.440 Hom.: 1154

Bravo AF: 0.615

Asia WGS AF: 0.694 AC: 2413 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KCNQ1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.5
DANN	Benign	0.48

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: rs7942590; hg19: chr11-2633715;