11-2777075-T-C

Variant names:

• chr11-2777075-T-C
• rs81204
• NM_000218.3:c.1732+43T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000218.3(KCNQ1):​c.1732+43T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,598,214 control chromosomes in the GnomAD database, including 43,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3606 hom., cov: 33)
  • Exomes 𝑓: 0.23 (39402 hom.)
• Consequence: KCNQ1 NM_000218.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.37
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-2777075-T-C is Benign according to our data. Variant chr11-2777075-T-C is described in ClinVar as Benign. ClinVar VariationId is 1291253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 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.1732+43T>C		intron	N/A	NP_000209.2
	KCNQ1	NM_001406836.1		c.1636+43T>C		intron	N/A	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1462+43T>C		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.1732+43T>C		intron	N/A	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.1351+43T>C		intron	N/A	ENSP00000334497.5
	KCNQ1	ENST00000713725.1		c.1591+43T>C		intron	N/A	ENSP00000519029.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32248 AN: 151962 Hom.: 3596 Cov.: 33

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.226 AC: 55693 AN: 246608 AF XY: 0.228

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.267

Gnomad FIN exome AF: 0.252

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.232 AC: 335677 AN: 1446134 Hom.: 39402 Cov.: 29 AF XY: 0.232 AC XY: 167115 AN XY: 720132

African (AFR) AF: 0.140 AC: 4654 AN: 33138

American (AMR) AF: 0.197 AC: 8755 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5922 AN: 26016

East Asian (EAS) AF: 0.224 AC: 8872 AN: 39558

South Asian (SAS) AF: 0.221 AC: 18927 AN: 85578

European-Finnish (FIN) AF: 0.254 AC: 13520 AN: 53238

Middle Eastern (MID) AF: 0.180 AC: 1033 AN: 5746

European-Non Finnish (NFE) AF: 0.237 AC: 259814 AN: 1098512

Other (OTH) AF: 0.237 AC: 14180 AN: 59888

GnomAD4 genome AF: 0.212 AC: 32300 AN: 152080 Hom.: 3606 Cov.: 33 AF XY: 0.213 AC XY: 15814 AN XY: 74328

African (AFR) AF: 0.144 AC: 5977 AN: 41480

American (AMR) AF: 0.225 AC: 3435 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 783 AN: 3470

East Asian (EAS) AF: 0.258 AC: 1332 AN: 5160

South Asian (SAS) AF: 0.221 AC: 1067 AN: 4818

European-Finnish (FIN) AF: 0.253 AC: 2675 AN: 10576

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16232 AN: 67984

Other (OTH) AF: 0.242 AC: 508 AN: 2102

Alfa AF: 0.226 Hom.: 5479

Bravo AF: 0.205

Asia WGS AF: 0.292 AC: 1016 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.052
DANN	Benign	0.49
PhyloP100		-3.4
PromoterAI		0.0016	Neutral
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: rs81204; hg19: chr11-2798305; COSMIC: COSV50112501; COSMIC: COSV50112501;