Genetic Variant KCNH2:c.76+8G>C (chr7-150977830-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000238.4(KCNH2):c.76+8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 splice_region, intron

Scores

Splicing: ADA: 0.01143

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0450

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.76+8G>C	splice_region_variant, intron_variant	Intron 1 of 14	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0
KCNH2	NM_172056.3 link	c.76+8G>C	splice_region_variant, intron_variant	Intron 1 of 8		NP_742053.1	Q12809-5A0A090N7W1Q15BH2
KCNH2	NR_176254.1 link	n.484+8G>C	splice_region_variant, intron_variant	Intron 1 of 14

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNH2	ENST00000262186.10 link	c.76+8G>C	splice_region_variant, intron_variant	Intron 1 of 14	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000713710.1 link	c.76+8G>C	splice_region_variant, intron_variant	Intron 1 of 14			ENSP00000519013.1
KCNH2	ENST00000532957.5 link	n.299+8G>C	splice_region_variant, intron_variant	Intron 1 of 8	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000446

AC:

AN:

224218

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437362

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32962

American (AMR)

AF:

0.00

AC:

AN:

43718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25810

East Asian (EAS)

AF:

0.00

AC:

AN:

39182

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098186

Other (OTH)

AF:

0.00

AC:

AN:

59442

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

-0.045

PromoterAI

-0.049

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.011

dbscSNV1_RF

Benign

0.046

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over