11-2572049-C-T

Variant names:

• chr11-2572049-C-T
• rs28730754
• NM_000218.3:c.720C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000218.3(KCNQ1):​c.720C>T​(p.His240His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,612,882 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (4 hom.)
• Consequence: KCNQ1 NM_000218.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -2.42
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 11-2572049-C-T is Benign according to our data. Variant chr11-2572049-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000641 (937/1460646) while in subpopulation AFR AF = 0.0168 (562/33474). AF 95% confidence interval is 0.0156. There are 4 homozygotes in GnomAdExome4. There are 405 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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.720C>T	p.His240His	synonymous	Exon 5 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.720C>T	p.His240His	synonymous	Exon 5 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.450C>T	p.His150His	synonymous	Exon 6 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.720C>T	p.His240His	synonymous	Exon 5 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.339C>T	p.His113His	synonymous	Exon 5 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.717C>T	p.His239His	synonymous	Exon 5 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.00483 AC: 734 AN: 152118 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00158 AC: 394 AN: 249054 AF XY: 0.00119

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000283

Gnomad NFE exome AF: 0.000436

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000641 AC: 937 AN: 1460646 Hom.: 4 Cov.: 31 AF XY: 0.000557 AC XY: 405 AN XY: 726642

African (AFR) AF: 0.0168 AC: 562 AN: 33474

American (AMR) AF: 0.00190 AC: 85 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86248

European-Finnish (FIN) AF: 0.000210 AC: 11 AN: 52376

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.000157 AC: 175 AN: 1111878

Other (OTH) AF: 0.00149 AC: 90 AN: 60374

GnomAD4 genome AF: 0.00482 AC: 734 AN: 152236 Hom.: 1 Cov.: 33 AF XY: 0.00447 AC XY: 333 AN XY: 74424

African (AFR) AF: 0.0156 AC: 650 AN: 41548

American (AMR) AF: 0.00327 AC: 50 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68002

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00241 Hom.: 0

Bravo AF: 0.00573

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Long QT syndrome (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	Long QT syndrome 1 (1)
-	-	1	Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.39
DANN	Benign	0.67
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism

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: rs28730754; hg19: chr11-2593279; COSMIC: COSV99325678;