Genetic Variant KCNH2:c.307+1932G>C (chr7-150972779-C-G) – 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+1932G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,156 control chromosomes in the GnomAD database, including 4,061 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 0.22 ( 4061 hom., cov: 33)

Consequence

KCNH2
NM_000238.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.465

Publications

10 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 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+1932G>C	intron	N/A	NP_000229.1	A0A090N8Q0
KCNH2	NM_172056.3		c.307+1932G>C	intron	N/A	NP_742053.1	Q12809-5
KCNH2	NM_001406755.1		c.130+1932G>C	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+1932G>C	intron	N/A	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000713710.1		c.307+1932G>C	intron	N/A	ENSP00000519013.1	A0AAQ5BGR0
KCNH2	ENST00000713701.1		c.7+1591G>C	intron	N/A	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes

AF:

0.217

AC:

32970

AN:

152038

Hom.:

4058

Cov.:

show subpopulations

Gnomad AFR

AF:

0.315

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.220

Gnomad EAS

AF:

0.319

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.168

Gnomad OTH

AF:

0.193

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

GnomAD4 genome

AF:

0.217

AC:

32985

AN:

152156

Hom.:

4061

Cov.:

AF XY:

0.218

AC XY:

16223

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.315

AC:

13051

AN:

41472

American (AMR)

AF:

0.121

AC:

1854

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

763

AN:

3472

East Asian (EAS)

AF:

0.319

AC:

1652

AN:

5184

South Asian (SAS)

AF:

0.200

AC:

967

AN:

4830

European-Finnish (FIN)

AF:

0.251

AC:

2657

AN:

10590

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.168

AC:

11445

AN:

68000

Other (OTH)

AF:

0.194

AC:

410

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1320

2639

3959

5278

6598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.0950

Hom.:

152

Bravo

AF:

0.214

Asia WGS

AF:

0.236

AC:

822

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

3.2

(source)

DANN

Benign

0.41

PhyloP100

-0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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