11-2459471-C-G

Variant names:

• chr11-2459471-C-G
• rs7951832
• NM_000218.3:c.386+13987C>G

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+13987C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 152,052 control chromosomes in the GnomAD database, including 13,554 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 0.36 (13554 hom., cov: 32)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0830
• Publications: 6 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
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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)
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 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+13987C>G		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.386+13987C>G		intron	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.24+13987C>G		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+13987C>G		intron	N/A	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000345015.4	TSL:1	n.163+13987C>G		intron	N/A
	KCNQ1	ENST00000910997.1		c.386+13987C>G		intron	N/A	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53995 AN: 151934 Hom.: 13506 Cov.: 32

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.335

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

GnomAD4 genome AF: 0.356 AC: 54094 AN: 152052 Hom.: 13554 Cov.: 32 AF XY: 0.360 AC XY: 26721 AN XY: 74322

African (AFR) AF: 0.701 AC: 29057 AN: 41456

American (AMR) AF: 0.361 AC: 5521 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 921 AN: 3470

East Asian (EAS) AF: 0.358 AC: 1845 AN: 5158

South Asian (SAS) AF: 0.336 AC: 1618 AN: 4818

European-Finnish (FIN) AF: 0.251 AC: 2653 AN: 10588

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11563 AN: 67964

Other (OTH) AF: 0.336 AC: 707 AN: 2106

Alfa AF: 0.116 Hom.: 187

Bravo AF: 0.380

Asia WGS AF: 0.441 AC: 1530 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.43
PhyloP100		0.083
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: rs7951832; hg19: chr11-2480701;