NM_000218.3:c.1514+6235T>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
• Publications: 12 publications found

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]

KCNQ1OT1 Gene-Disease associations (from GenCC):

• Beckwith-Wiedemann syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1514+6235T>C		intron	N/A	NP_000209.2
	KCNQ1OT1	NR_002728.4	MANE Select	n.31679A>G		non_coding_transcript_exon	Exon 1 of 1
	KCNQ1	NM_001406836.1		c.1418+6235T>C		intron	N/A	NP_001393765.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1514+6235T>C		intron	N/A	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1133+6235T>C		intron	N/A	ENSP00000334497.5	P51787-2
	KCNQ1OT1	ENST00000597346.1	TSL:6 MANE Select	n.31679A>G		non_coding_transcript_exon	Exon 1 of 1

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

African (AFR) AF: 0.446 AC: 3206 AN: 7182

American (AMR) AF: 0.221 AC: 1645 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 2902 AN: 9240

East Asian (EAS) AF: 0.0660 AC: 1512 AN: 22894

South Asian (SAS) AF: 0.272 AC: 825 AN: 3032

European-Finnish (FIN) AF: 0.195 AC: 4068 AN: 20826

Middle Eastern (MID) AF: 0.275 AC: 356 AN: 1294

European-Non Finnish (NFE) AF: 0.228 AC: 36115 AN: 158058

Other (OTH) 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

African (AFR) AF: 0.454 AC: 18796 AN: 41430

American (AMR) AF: 0.229 AC: 3506 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1072 AN: 3470

East Asian (EAS) AF: 0.0915 AC: 474 AN: 5178

South Asian (SAS) AF: 0.270 AC: 1303 AN: 4822

European-Finnish (FIN) AF: 0.190 AC: 2011 AN: 10590

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15225 AN: 67986

Other (OTH) AF: 0.268 AC: 567 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.56
PhyloP100		0.12
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

Other links and lift over

dbSNP: rs1459825; hg19: chr11-2689546;