Genetic Variant KCNH5:p.Arg859Arg (chr14-62707898-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_139318.5(KCNH5):c.2577A>G(p.Arg859Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.981 in 1,614,112 control chromosomes in the GnomAD database, including 777,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 67074 hom., cov: 31)

Exomes 𝑓: 0.99 ( 710712 hom. )

Consequence

KCNH5
NM_139318.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.932

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 14-62707898-T-C is Benign according to our data. Variant chr14-62707898-T-C is described in ClinVar as [Benign]. Clinvar id is 1166142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.932 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5 link	c.2577A>G	p.Arg859Arg	synonymous_variant	Exon 11 of 11	ENST00000322893.12	NP_647479.2	Q8NCM2-1
KCNH5	NM_172375.3 link	c.*544A>G		3_prime_UTR_variant	Exon 10 of 10		NP_758963.1	Q8NCM2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12 link	c.2577A>G	p.Arg859Arg	synonymous_variant	Exon 11 of 11	1	NM_139318.5	ENSP00000321427.7		Q8NCM2-1
KCNH5	ENST00000420622 link	c.*544A>G		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000395439.2		Q8NCM2-2

Frequencies

GnomAD3 genomes

AF:

0.935

AC:

142202

AN:

152104

Hom.:

67039

Cov.:

show subpopulations

Gnomad AFR

AF:

0.798

Gnomad AMI

AF:

0.996

Gnomad AMR

AF:

0.963

Gnomad ASJ

AF:

0.971

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.981

Gnomad FIN

AF:

0.996

Gnomad MID

AF:

0.965

Gnomad NFE

AF:

0.991

Gnomad OTH

AF:

0.938

GnomAD3 exomes

AF:

0.976

AC:

245352

AN:

251490

Hom.:

119997

AF XY:

0.979

AC XY:

133040

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.793

Gnomad AMR exome

AF:

0.980

Gnomad ASJ exome

AF:

0.972

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.980

Gnomad FIN exome

AF:

0.996

Gnomad NFE exome

AF:

0.991

Gnomad OTH exome

AF:

0.978

GnomAD4 exome

AF:

0.986

AC:

1440752

AN:

1461890

Hom.:

710712

Cov.:

AF XY:

0.986

AC XY:

716977

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.787

Gnomad4 AMR exome

AF:

0.979

Gnomad4 ASJ exome

AF:

0.972

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.981

Gnomad4 FIN exome

AF:

0.997

Gnomad4 NFE exome

AF:

0.992

Gnomad4 OTH exome

AF:

0.977

GnomAD4 genome

AF:

0.935

AC:

142289

AN:

152222

Hom.:

67074

Cov.:

AF XY:

0.936

AC XY:

69680

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.797

Gnomad4 AMR

AF:

0.964

Gnomad4 ASJ

AF:

0.971

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.982

Gnomad4 FIN

AF:

0.996

Gnomad4 NFE

AF:

0.991

Gnomad4 OTH

AF:

0.940

Alfa

AF:

0.973

Hom.:

86054

Bravo

AF:

0.927

Asia WGS

AF:

0.977

AC:

3394

AN:

3478

EpiCase

AF:

0.989

EpiControl

AF:

0.988

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.9

DANN

Benign

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over