rs17215465

Variant names:

• chr11-2662022-C-T
• rs17215465
• NM_000218.3:c.1455C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000218.3(KCNQ1):​c.1455C>T​(p.Phe485Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,614,202 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene KCNQ1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (76 hom.)
• Consequence: KCNQ1 NM_000218.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -1.20
• Publications: 3 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

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 11-2662022-C-T is Benign according to our data. Variant chr11-2662022-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0145 (2207/152320) while in subpopulation AFR AF = 0.0474 (1971/41558). AF 95% confidence interval is 0.0457. There are 49 homozygotes in GnomAd4. There are 1020 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AD,AR gene

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.1455C>T	p.Phe485Phe	synonymous	Exon 11 of 16	NP_000209.2
	KCNQ1OT1	NR_002728.4	MANE Select	n.37973G>A		non_coding_transcript_exon	Exon 1 of 1
	KCNQ1	NM_001406836.1		c.1359C>T	p.Phe453Phe	synonymous	Exon 10 of 15	NP_001393765.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1455C>T	p.Phe485Phe	synonymous	Exon 11 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1074C>T	p.Phe358Phe	synonymous	Exon 11 of 16	ENSP00000334497.5	P51787-2
	KCNQ1OT1	ENST00000597346.1	TSL:6 MANE Select	n.37973G>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2203 AN: 152202 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00521 AC: 1310 AN: 251402 AF XY: 0.00448

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.000652

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00259 AC: 3781 AN: 1461882 Hom.: 76 Cov.: 34 AF XY: 0.00264 AC XY: 1920 AN XY: 727240

African (AFR) AF: 0.0502 AC: 1682 AN: 33480

American (AMR) AF: 0.00277 AC: 124 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26136

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39700

South Asian (SAS) AF: 0.00845 AC: 729 AN: 86258

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53412

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.000814 AC: 905 AN: 1112008

Other (OTH) AF: 0.00421 AC: 254 AN: 60396

GnomAD4 genome AF: 0.0145 AC: 2207 AN: 152320 Hom.: 49 Cov.: 33 AF XY: 0.0137 AC XY: 1020 AN XY: 74486

African (AFR) AF: 0.0474 AC: 1971 AN: 41558

American (AMR) AF: 0.00588 AC: 90 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68026

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.00832 Hom.: 23

Bravo AF: 0.0166

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Long QT syndrome (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	Long QT syndrome 1 (1)
-	-	1	Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.1
DANN	Benign	0.69
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs17215465; hg19: chr11-2683252; COSMIC: COSV50120135;