11-2529500-A-G

Variant names:

• chr11-2529500-A-G
• rs179429
• NM_000218.3:c.477+1482A>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.477+1482A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.831 in 151,908 control chromosomes in the GnomAD database, including 52,578 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 0.83 (52578 hom., cov: 28)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.578
• Publications: 20 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• 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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.95 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.477+1482A>G		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.477+1482A>G		intron	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.207+1482A>G		intron	N/A	NP_001393766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.477+1482A>G		intron	N/A	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.96+1482A>G		intron	N/A	ENSP00000334497.5
	KCNQ1	ENST00000713725.1		c.477+1482A>G		intron	N/A	ENSP00000519029.1

Frequencies

GnomAD3 genomes AF: 0.831 AC: 126106 AN: 151790 Hom.: 52516 Cov.: 28

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.780

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.841

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.815

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

GnomAD4 genome AF: 0.831 AC: 126220 AN: 151908 Hom.: 52578 Cov.: 28 AF XY: 0.832 AC XY: 61792 AN XY: 74236

African (AFR) AF: 0.809 AC: 33496 AN: 41408

American (AMR) AF: 0.867 AC: 13248 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 2709 AN: 3472

East Asian (EAS) AF: 0.973 AC: 5007 AN: 5148

South Asian (SAS) AF: 0.808 AC: 3882 AN: 4804

European-Finnish (FIN) AF: 0.841 AC: 8878 AN: 10552

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.828 AC: 56218 AN: 67930

Other (OTH) AF: 0.817 AC: 1725 AN: 2112

Alfa AF: 0.831 Hom.: 246541

Bravo AF: 0.835

Asia WGS AF: 0.906 AC: 3148 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.65
DANN	Benign	0.36
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs179429; hg19: chr11-2550730;