Genetic Variant KCNH5:p.Arg154Arg (chr14-62987161-G-T) – 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_139318.5(KCNH5):c.460C>A(p.Arg154Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000137 in 1,461,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R154R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNH5
NM_139318.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.87

Publications

0 publications found

Variant links:

Genes affected

KCNH5 (HGNC:6254): (potassium voltage-gated channel subfamily H member 5) This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

KCNH5 Gene-Disease associations (from GenCC):

infantile-onset epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy 112
Inheritance: AD Classification: STRONG Submitted by: G2P

KCNH5 links:

Genome browser will be placed here

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=-0.35).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KCNH5	NM_139318.5 link	c.460C>A	p.Arg154Arg	synonymous_variant	Exon 5 of 11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3 link	c.460C>A	p.Arg154Arg	synonymous_variant	Exon 5 of 10		NP_758963.1
KCNH5	XM_047431275.1 link	c.460C>A	p.Arg154Arg	synonymous_variant	Exon 5 of 10		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KCNH5	ENST00000322893.12 link	c.460C>A	p.Arg154Arg	synonymous_variant	Exon 5 of 11	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6 link	c.460C>A	p.Arg154Arg	synonymous_variant	Exon 5 of 10	1		ENSP00000395439.2
KCNH5	ENST00000394964.3 link	n.625C>A		non_coding_transcript_exon_variant	Exon 5 of 7	1
KCNH5	ENST00000394968.2 link	c.286C>A	p.Arg96Arg	synonymous_variant	Exon 5 of 11	2		ENSP00000378419.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461188

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726870

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111534

Other (OTH)

AF:

0.00

AC:

AN:

60370

⚠️ 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: 0.350

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

9.5

(source)

DANN

Benign

0.56

PhyloP100

3.9

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over