Genetic Variant KCNH2:n.1699A>C (chr7-150950165-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The ENST00000461280.2(KCNH2):n.1699A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. 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 0.000040 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNH2
ENST00000461280.2 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.69

Publications

1 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), Ambry Genetics, G2P
short QT syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
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: Uncertain_significance. The variant received 2 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000461280.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNH2	NM_000238.4	MANE Select	c.2398+3A>C		splice_region intron	N/A	NP_000229.1
KCNH2	NM_172056.3		c.2401A>C	p.Met801Leu	missense	Exon 9 of 9	NP_742053.1
KCNH2	NM_001406755.1		c.2224A>C	p.Met742Leu	missense	Exon 9 of 9	NP_001393684.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KCNH2	ENST00000461280.2	TSL:1	n.1699A>C	non_coding_transcript_exon	Exon 5 of 5
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2398+3A>C	splice_region intron	N/A	ENSP00000262186.5
KCNH2	ENST00000330883.9	TSL:1	c.1378+3A>C	splice_region intron	N/A	ENSP00000328531.4

Frequencies

GnomAD3 genomes

AF:

0.0000400

AC:

AN:

124990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000298

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000266

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000339

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000130

AC:

AN:

609120

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

325108

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000126

AC:

AN:

15864

American (AMR)

AF:

0.000103

AC:

AN:

38656

Ashkenazi Jewish (ASJ)

AF:

0.000126

AC:

AN:

15904

East Asian (EAS)

AF:

0.000268

AC:

AN:

22358

South Asian (SAS)

AF:

0.0000142

AC:

AN:

70408

European-Finnish (FIN)

AF:

0.000266

AC:

AN:

37548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3584

European-Non Finnish (NFE)

AF:

0.000127

AC:

AN:

377962

Other (OTH)

AF:

0.000224

AC:

AN:

26836

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.247

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000400

AC:

AN:

125042

Hom.:

Cov.:

AF XY:

0.0000497

AC XY:

AN XY:

60350

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000298

AC:

AN:

33564

American (AMR)

AF:

0.00

AC:

AN:

12422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3078

East Asian (EAS)

AF:

0.00

AC:

AN:

3502

South Asian (SAS)

AF:

0.00

AC:

AN:

3032

European-Finnish (FIN)

AF:

0.000266

AC:

AN:

7530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.0000339

AC:

AN:

59072

Other (OTH)

AF:

0.00

AC:

AN:

1796

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.265

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.21

MetaSVM

Uncertain

0.13

PhyloP100

2.7

REVEL

Uncertain

0.39

Sift4G

Uncertain

0.017

Vest4

0.30

MVP

0.26

ClinPred

0.70

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.87

Position offset: 3

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