11-2468112-C-T

Variant names:

• chr11-2468112-C-T
• rs12296050
• NM_000218.3:c.386+22628C>T

Variant summary

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

The NM_000218.3(KCNQ1):​c.386+22628C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 152,202 control chromosomes in the GnomAD database, including 9,495 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. The gene KCNQ1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.32 (9495 hom., cov: 33)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217
• Publications: 50 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]

KCNQ1 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• long QT syndrome 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 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.386+22628C>T		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.386+22628C>T		intron	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.24+22628C>T		intron	N/A	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.386+22628C>T		intron	N/A	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.5+6398C>T		intron	N/A	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000345015.4	TSL:1	n.163+22628C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49062 AN: 152084 Hom.: 9447 Cov.: 33

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.296

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.323 AC: 49167 AN: 152202 Hom.: 9495 Cov.: 33 AF XY: 0.331 AC XY: 24602 AN XY: 74416

African (AFR) AF: 0.526 AC: 21823 AN: 41522

American (AMR) AF: 0.355 AC: 5438 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 887 AN: 3466

East Asian (EAS) AF: 0.355 AC: 1830 AN: 5162

South Asian (SAS) AF: 0.361 AC: 1740 AN: 4826

European-Finnish (FIN) AF: 0.307 AC: 3258 AN: 10606

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13194 AN: 68006

Other (OTH) AF: 0.298 AC: 628 AN: 2110

Alfa AF: 0.238 Hom.: 15250

Bravo AF: 0.336

Asia WGS AF: 0.452 AC: 1568 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.92
DANN	Benign	0.35
PhyloP100		-0.22
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs12296050;

hg19: chr11-2489342;