11-2669301-T-C

Variant names:

• chr11-2669301-T-C
• rs4930005
• NM_000218.3:c.1514+7220T>C

Variant summary

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

The NM_000218.3(KCNQ1):​c.1514+7220T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 398,432 control chromosomes in the GnomAD database, including 13,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.27 (5864 hom., cov: 32)
  • Exomes 𝑓: 0.24 (7623 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.176

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=-0.9).
• BP6: Variant 11-2669301-T-C is Benign according to our data. Variant chr11-2669301-T-C is described in ClinVar as [Benign]. Clinvar id is 3059037.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1514+7220T>C		intron_variant	Intron 11 of 15	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1514+7220T>C		intron_variant	Intron 11 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40854 AN: 152000 Hom.: 5856 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.0885

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.238 AC: 58697 AN: 246314 Hom.: 7623 Cov.: 0 AF XY: 0.239 AC XY: 29780 AN XY: 124806

Gnomad4 AFR exome AF: 0.350

Gnomad4 AMR exome AF: 0.236

Gnomad4 ASJ exome AF: 0.367

Gnomad4 EAS exome AF: 0.0639

Gnomad4 SAS exome AF: 0.287

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.268

GnomAD4 genome AF: 0.269 AC: 40910 AN: 152118 Hom.: 5864 Cov.: 32 AF XY: 0.265 AC XY: 19707 AN XY: 74398

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.0887

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.274

Alfa AF: 0.256 Hom.: 1792

Bravo AF: 0.277

Asia WGS AF: 0.225 AC: 781 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KCNQ1-related disorder Benign:1

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	-0.90
CADD	Benign	1.6
DANN	Benign	0.62

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: rs4930005; hg19: chr11-2690531;