chr11-2669301-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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 -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1514+7220T>C		intron	N/A	NP_000209.2
	KCNQ1OT1	NR_002728.4	MANE Select	n.30694A>G		non_coding_transcript_exon	Exon 1 of 1
	KCNQ1	NM_001406836.1		c.1418+7220T>C		intron	N/A	NP_001393765.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1514+7220T>C		intron	N/A	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.1133+7220T>C		intron	N/A	ENSP00000334497.5
	KCNQ1OT1	ENST00000597346.1	TSL:6 MANE Select	n.30694A>G		non_coding_transcript_exon	Exon 1 of 1

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

African (AFR) AF: 0.350 AC: 2516 AN: 7180

American (AMR) AF: 0.236 AC: 1757 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 3393 AN: 9240

East Asian (EAS) AF: 0.0639 AC: 1462 AN: 22894

South Asian (SAS) AF: 0.287 AC: 871 AN: 3032

European-Finnish (FIN) AF: 0.207 AC: 4305 AN: 20824

Middle Eastern (MID) AF: 0.317 AC: 410 AN: 1294

European-Non Finnish (NFE) AF: 0.250 AC: 39588 AN: 158046

Other (OTH) AF: 0.268 AC: 4395 AN: 16370

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

African (AFR) AF: 0.348 AC: 14435 AN: 41462

American (AMR) AF: 0.241 AC: 3682 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1252 AN: 3468

East Asian (EAS) AF: 0.0887 AC: 460 AN: 5184

South Asian (SAS) AF: 0.283 AC: 1367 AN: 4822

European-Finnish (FIN) AF: 0.203 AC: 2154 AN: 10600

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16572 AN: 67976

Other (OTH) AF: 0.274 AC: 578 AN: 2108

Alfa AF: 0.254 Hom.: 3471

Bravo AF: 0.277

Asia WGS AF: 0.225 AC: 781 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KCNQ1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.62
PhyloP100		-0.18
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: rs4930005; hg19: chr11-2690531;