dbSNP rs142666361: KCNH5:p.Leu259Leu (chr14-62981039-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_139318.5(KCNH5):c.775C>T(p.Leu259Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,614,140 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

KCNH5
NM_139318.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.07

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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 14-62981039-G-A is Benign according to our data. Variant chr14-62981039-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00236 (360/152276) while in subpopulation AFR AF = 0.00818 (340/41554). AF 95% confidence interval is 0.00747. There are 1 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 360 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139318.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	NM_139318.5	MANE Select	c.775C>T	p.Leu259Leu	synonymous	Exon 6 of 11	NP_647479.2
	KCNH5	NM_172375.3		c.775C>T	p.Leu259Leu	synonymous	Exon 6 of 10	NP_758963.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNH5	ENST00000322893.12	TSL:1 MANE Select	c.775C>T	p.Leu259Leu	synonymous	Exon 6 of 11	ENSP00000321427.7
KCNH5	ENST00000420622.6	TSL:1	c.775C>T	p.Leu259Leu	synonymous	Exon 6 of 10	ENSP00000395439.2
KCNH5	ENST00000394964.3	TSL:1	n.940C>T		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes

AF:

0.00236

AC:

359

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00818

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000525

AC:

132

AN:

251306

AF XY:

0.000361

show subpopulations

Gnomad AFR exome

AF:

0.00707

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000234

AC:

342

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

145

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00839

AC:

281

AN:

33480

American (AMR)

AF:

0.000514

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1112002

Other (OTH)

AF:

0.000464

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.00236

AC:

360

AN:

152276

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

167

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00818

AC:

340

AN:

41554

American (AMR)

AF:

0.00105

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68014

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00249

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNH5: BP4, BS1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Developmental and epileptic encephalopathy

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.0

(source)

DANN

Benign

0.73

PhyloP100

2.1

Mutation Taster

=87/13

polymorphism

(source)

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

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over