dbSNP rs1805121: KCNH2:p.Leu564Leu (chr7-150951701-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000238.4(KCNH2):c.1692A>G(p.Leu564Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,613,944 control chromosomes in the GnomAD database, including 154,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 22197 hom., cov: 36)

Exomes 𝑓: 0.41 ( 132576 hom. )

Consequence

KCNH2
NM_000238.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 2.05

Publications

26 publications found

Variant links:

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

KCNH2 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
short QT syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
short QT syndrome type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 7-150951701-T-C is Benign according to our data. Variant chr7-150951701-T-C is described in ClinVar as Benign. ClinVar VariationId is 200228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNH2	NM_000238.4	MANE Select	c.1692A>G	p.Leu564Leu	synonymous	Exon 7 of 15	NP_000229.1	A0A090N8Q0
KCNH2	NM_001406753.1		c.1404A>G	p.Leu468Leu	synonymous	Exon 5 of 13	NP_001393682.1	Q12809-7
KCNH2	NM_172056.3		c.1692A>G	p.Leu564Leu	synonymous	Exon 7 of 9	NP_742053.1	Q12809-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1692A>G	p.Leu564Leu	synonymous	Exon 7 of 15	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9	TSL:1	c.672A>G	p.Leu224Leu	synonymous	Exon 3 of 11	ENSP00000328531.4	Q12809-2
KCNH2	ENST00000461280.2	TSL:1	n.990A>G		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes

AF:

0.512

AC:

77877

AN:

152126

Hom.:

22156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.742

Gnomad AMI

AF:

0.361

Gnomad AMR

AF:

0.480

Gnomad ASJ

AF:

0.415

Gnomad EAS

AF:

0.861

Gnomad SAS

AF:

0.466

Gnomad FIN

AF:

0.480

Gnomad MID

AF:

0.421

Gnomad NFE

AF:

0.369

Gnomad OTH

AF:

0.471

GnomAD2 exomes

AF:

0.479

AC:

120387

AN:

251176

AF XY:

0.468

show subpopulations

Gnomad AFR exome

AF:

0.759

Gnomad AMR exome

AF:

0.531

Gnomad ASJ exome

AF:

0.399

Gnomad EAS exome

AF:

0.868

Gnomad FIN exome

AF:

0.478

Gnomad NFE exome

AF:

0.374

Gnomad OTH exome

AF:

0.444

GnomAD4 exome

AF:

0.411

AC:

601273

AN:

1461700

Hom.:

132576

Cov.:

AF XY:

0.411

AC XY:

299172

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.761

AC:

25490

AN:

33480

American (AMR)

AF:

0.522

AC:

23359

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.397

AC:

10379

AN:

26136

East Asian (EAS)

AF:

0.896

AC:

35565

AN:

39696

South Asian (SAS)

AF:

0.471

AC:

40612

AN:

86252

European-Finnish (FIN)

AF:

0.467

AC:

24915

AN:

53366

Middle Eastern (MID)

AF:

0.419

AC:

2415

AN:

5764

European-Non Finnish (NFE)

AF:

0.371

AC:

412020

AN:

1111908

Other (OTH)

AF:

0.439

AC:

26518

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

24398

48796

73193

97591

121989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13382

26764

40146

53528

66910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.512

AC:

77979

AN:

152244

Hom.:

22197

Cov.:

AF XY:

0.518

AC XY:

38533

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.742

AC:

30815

AN:

41536

American (AMR)

AF:

0.481

AC:

7356

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

1441

AN:

3472

East Asian (EAS)

AF:

0.861

AC:

4458

AN:

5176

South Asian (SAS)

AF:

0.467

AC:

2254

AN:

4828

European-Finnish (FIN)

AF:

0.480

AC:

5088

AN:

10602

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.369

AC:

25108

AN:

68002

Other (OTH)

AF:

0.477

AC:

1009

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1838

3677

5515

7354

9192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

670

1340

2010

2680

3350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.440

Hom.:

7666

Bravo

AF:

0.527

Asia WGS

AF:

0.627

AC:

2180

AN:

3478

EpiCase

AF:

0.369

EpiControl

AF:

0.360

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Long QT syndrome (3)

Long QT syndrome 2 (2)

not provided (2)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over