rs1057128

Variant names:

• chr11-2776007-G-A
• rs1057128
• NM_000218.3:c.1638G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2776007-G-A
• chr11-2776007-G-T

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.1638G>A​(p.Ser546Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,572,900 control chromosomes in the GnomAD database, including 33,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S546S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2692 hom., cov: 33)
  • Exomes 𝑓: 0.20 (30787 hom.)
• Consequence: KCNQ1 NM_000218.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -2.43
• Publications: 42 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 11-2776007-G-A is Benign according to our data. Variant chr11-2776007-G-A is described in ClinVar as Benign. ClinVar VariationId is 42488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.28 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.1638G>A	p.Ser546Ser	synonymous	Exon 13 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1542G>A	p.Ser514Ser	synonymous	Exon 12 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1368G>A	p.Ser456Ser	synonymous	Exon 14 of 17	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1638G>A	p.Ser546Ser	synonymous	Exon 13 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1257G>A	p.Ser419Ser	synonymous	Exon 13 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1635G>A	p.Ser545Ser	synonymous	Exon 13 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25516 AN: 152110 Hom.: 2690 Cov.: 33

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.208 AC: 39074 AN: 187994 AF XY: 0.203

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.283

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.203 AC: 287746 AN: 1420672 Hom.: 30787 Cov.: 35 AF XY: 0.202 AC XY: 141579 AN XY: 702430

African (AFR) AF: 0.0363 AC: 1197 AN: 32978

American (AMR) AF: 0.353 AC: 13246 AN: 37548

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 4177 AN: 25334

East Asian (EAS) AF: 0.294 AC: 11155 AN: 37978

South Asian (SAS) AF: 0.182 AC: 14634 AN: 80606

European-Finnish (FIN) AF: 0.187 AC: 9365 AN: 50010

Middle Eastern (MID) AF: 0.165 AC: 941 AN: 5716

European-Non Finnish (NFE) AF: 0.203 AC: 221203 AN: 1091428

Other (OTH) AF: 0.200 AC: 11828 AN: 59074

GnomAD4 genome AF: 0.168 AC: 25520 AN: 152228 Hom.: 2692 Cov.: 33 AF XY: 0.169 AC XY: 12606 AN XY: 74428

African (AFR) AF: 0.0460 AC: 1912 AN: 41550

American (AMR) AF: 0.287 AC: 4382 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 546 AN: 3472

East Asian (EAS) AF: 0.291 AC: 1503 AN: 5166

South Asian (SAS) AF: 0.182 AC: 879 AN: 4830

European-Finnish (FIN) AF: 0.189 AC: 2001 AN: 10610

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13617 AN: 67992

Other (OTH) AF: 0.185 AC: 390 AN: 2112

Alfa AF: 0.192 Hom.: 8204

Bravo AF: 0.174

Asia WGS AF: 0.220 AC: 763 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Long QT syndrome (3)
-	-	2	Long QT syndrome 1 (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.5
DANN	Benign	0.93
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057128; hg19: chr11-2797237; COSMIC: COSV50111629; COSMIC: COSV50111629;