rs800336

Variant names:

• chr11-2451901-G-A
• rs800336
• NM_000218.3:c.386+6417G>A

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+6417G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 152,098 control chromosomes in the GnomAD database, including 28,321 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 0.56 (28321 hom., cov: 32)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.473
• Publications: 11 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.734 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.386+6417G>A		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.386+6417G>A		intron	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.24+6417G>A		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.386+6417G>A		intron	N/A	ENSP00000155840.2
	KCNQ1	ENST00000345015.4	TSL:1	n.163+6417G>A		intron	N/A
	KCNQ1	ENST00000713725.1		c.386+6417G>A		intron	N/A	ENSP00000519029.1

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84509 AN: 151980 Hom.: 28324 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.764

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.740

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.556 AC: 84499 AN: 152098 Hom.: 28321 Cov.: 32 AF XY: 0.556 AC XY: 41369 AN XY: 74352

African (AFR) AF: 0.164 AC: 6810 AN: 41512

American (AMR) AF: 0.622 AC: 9507 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2378 AN: 3468

East Asian (EAS) AF: 0.570 AC: 2936 AN: 5148

South Asian (SAS) AF: 0.478 AC: 2298 AN: 4812

European-Finnish (FIN) AF: 0.764 AC: 8093 AN: 10592

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.740 AC: 50296 AN: 67976

Other (OTH) AF: 0.579 AC: 1221 AN: 2108

Alfa AF: 0.664 Hom.: 97529

Bravo AF: 0.530

Asia WGS AF: 0.483 AC: 1679 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.3
DANN	Benign	0.66
PhyloP100		0.47
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: rs800336; hg19: chr11-2473131;