NM_000218.3:c.477+7007T>C

Variant names:

• chr11-2535025-T-C
• rs757086
• NM_000218.3:c.477+7007T>C

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+7007T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 152,076 control chromosomes in the GnomAD database, including 33,266 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 0.64 (33266 hom., cov: 33)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17
• 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]

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.773 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.477+7007T>C		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.477+7007T>C		intron	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.207+7007T>C		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.477+7007T>C		intron	N/A	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.96+7007T>C		intron	N/A	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.477+7007T>C		intron	N/A	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97490 AN: 151958 Hom.: 33258 Cov.: 33

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.792

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.649

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

GnomAD4 genome AF: 0.641 AC: 97515 AN: 152076 Hom.: 33266 Cov.: 33 AF XY: 0.647 AC XY: 48073 AN XY: 74316

African (AFR) AF: 0.389 AC: 16139 AN: 41486

American (AMR) AF: 0.752 AC: 11493 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2176 AN: 3470

East Asian (EAS) AF: 0.793 AC: 4078 AN: 5140

South Asian (SAS) AF: 0.666 AC: 3213 AN: 4826

European-Finnish (FIN) AF: 0.792 AC: 8382 AN: 10590

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.732 AC: 49765 AN: 67956

Other (OTH) AF: 0.653 AC: 1379 AN: 2112

Alfa AF: 0.699 Hom.: 15714

Bravo AF: 0.628

Asia WGS AF: 0.676 AC: 2351 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	0.32
DANN	Benign	0.63
PhyloP100		-2.2
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: rs757086; hg19: chr11-2556255;