Genetic Variant KCNH2:c.307+4589G>A (chr7-150970122-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000238.4(KCNH2):c.307+4589G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 151,972 control chromosomes in the GnomAD database, including 20,473 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 0.49 ( 20473 hom., cov: 31)

Consequence

KCNH2
NM_000238.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0530

Publications

61 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.758 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	Effect	Exon Rank	Protein	UniProt
KCNH2	NM_000238.4	MANE Select	c.307+4589G>A	intron	N/A	NP_000229.1	A0A090N8Q0
KCNH2	NM_172056.3		c.307+4589G>A	intron	N/A	NP_742053.1	Q12809-5
KCNH2	NM_001406755.1		c.130+4589G>A	intron	N/A	NP_001393684.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.307+4589G>A	intron	N/A	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000713710.1		c.307+4589G>A	intron	N/A	ENSP00000519013.1	A0AAQ5BGR0
KCNH2	ENST00000713701.1		c.7+4248G>A	intron	N/A	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes

AF:

0.494

AC:

74983

AN:

151854

Hom.:

20424

Cov.:

show subpopulations

Gnomad AFR

AF:

0.706

Gnomad AMI

AF:

0.357

Gnomad AMR

AF:

0.510

Gnomad ASJ

AF:

0.380

Gnomad EAS

AF:

0.778

Gnomad SAS

AF:

0.411

Gnomad FIN

AF:

0.456

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.360

Gnomad OTH

AF:

0.459

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

GnomAD4 genome

AF:

0.494

AC:

75093

AN:

151972

Hom.:

20473

Cov.:

AF XY:

0.499

AC XY:

37096

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.706

AC:

29253

AN:

41458

American (AMR)

AF:

0.511

AC:

7801

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.380

AC:

1318

AN:

3468

East Asian (EAS)

AF:

0.778

AC:

4004

AN:

5148

South Asian (SAS)

AF:

0.413

AC:

1986

AN:

4814

European-Finnish (FIN)

AF:

0.456

AC:

4821

AN:

10564

Middle Eastern (MID)

AF:

0.415

AC:

122

AN:

294

European-Non Finnish (NFE)

AF:

0.360

AC:

24483

AN:

67938

Other (OTH)

AF:

0.465

AC:

982

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1770

3540

5310

7080

8850

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

652

1304

1956

2608

3260

<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:

0.415

Hom.:

48894

Bravo

AF:

0.514

Asia WGS

AF:

0.590

AC:

2049

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

2.6

(source)

DANN

Benign

0.71

PhyloP100

-0.053

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over