chr11-2668316-T-C

Variant names:

• chr11-2668316-T-C
• rs1459825
• NM_000218.3:c.1514+6235T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000218.3(KCNQ1):​c.1514+6235T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 398,420 control chromosomes in the GnomAD database, including 13,894 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (7116 hom., cov: 32)
  • Exomes 𝑓: 0.22 (6778 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.121

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1514+6235T>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+6235T>C		intron_variant	Intron 11 of 15	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43166 AN: 151964 Hom.: 7101 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.0913

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.223 AC: 54813 AN: 246338 Hom.: 6778 Cov.: 0 AF XY: 0.221 AC XY: 27607 AN XY: 124826

Gnomad4 AFR exome AF: 0.446 AC: 3206 AN: 7182

Gnomad4 AMR exome AF: 0.221 AC: 1645 AN: 7434

Gnomad4 ASJ exome AF: 0.314 AC: 2902 AN: 9240

Gnomad4 EAS exome AF: 0.0660 AC: 1512 AN: 22894

Gnomad4 SAS exome AF: 0.272 AC: 825 AN: 3032

Gnomad4 FIN exome AF: 0.195 AC: 4068 AN: 20826

Gnomad4 NFE exome AF: 0.228 AC: 36115 AN: 158058

Gnomad4 Remaining exome AF: 0.255 AC: 4184 AN: 16378

GnomAD4 genome AF: 0.284 AC: 43231 AN: 152082 Hom.: 7116 Cov.: 32 AF XY: 0.279 AC XY: 20775 AN XY: 74344

Gnomad4 AFR AF: 0.454 AC: 0.453681 AN: 0.453681

Gnomad4 AMR AF: 0.229 AC: 0.22927 AN: 0.22927

Gnomad4 ASJ AF: 0.309 AC: 0.308934 AN: 0.308934

Gnomad4 EAS AF: 0.0915 AC: 0.0915411 AN: 0.0915411

Gnomad4 SAS AF: 0.270 AC: 0.27022 AN: 0.27022

Gnomad4 FIN AF: 0.190 AC: 0.189896 AN: 0.189896

Gnomad4 NFE AF: 0.224 AC: 0.223943 AN: 0.223943

Gnomad4 OTH AF: 0.268 AC: 0.268212 AN: 0.268212

Alfa AF: 0.245 Hom.: 16654

Bravo AF: 0.297

Asia WGS AF: 0.217 AC: 756 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.56
Mutation Taster		=100/0	polymorphism (auto)

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: rs1459825; hg19: chr11-2689546;