Genetic Variant NM_139318.5:c.2890C>A (chr14-62707585-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_139318.5(KCNH5):c.2890C>A(p.Gln964Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,375,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q964E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

KCNH5
NM_139318.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.34

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15771776).

BP6

Variant 14-62707585-G-T is Benign according to our data. Variant chr14-62707585-G-T is described in ClinVar as [Benign]. Clinvar id is 241863.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5 link	c.2890C>A	p.Gln964Lys	missense_variant	Exon 11 of 11	ENST00000322893.12	NP_647479.2	Q8NCM2-1
KCNH5	NM_172375.3 link	c.*857C>A		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.2890C>A	p.Gln964Lys	missense_variant	Exon 11 of 11	1	NM_139318.5	ENSP00000321427.7		Q8NCM2-1
KCNH5	ENST00000420622.6 link	c.*857C>A		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000395439.2		Q8NCM2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000103

AC:

AN:

194438

AF XY:

0.0000195

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:

0.0000217

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000218

AC:

AN:

1375954

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

673614

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30864

American (AMR)

AF:

0.00

AC:

AN:

33976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21014

East Asian (EAS)

AF:

0.00

AC:

AN:

38734

South Asian (SAS)

AF:

0.00

AC:

AN:

70882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50548

Middle Eastern (MID)

AF:

0.000187

AC:

AN:

5352

European-Non Finnish (NFE)

AF:

0.0000253

AC:

AN:

1067828

Other (OTH)

AF:

0.0000352

AC:

AN:

56756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Benign:1

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.085

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.0098

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.67

M_CAP

Benign

0.074

MetaRNN

Benign

0.16

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

0.14

PhyloP100

7.3

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.040

REVEL

Uncertain

0.41

Sift

Benign

0.35

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.23

MutPred

0.32

Gain of catalytic residue at P966 (P = 0);

MVP

0.51

MPC

0.14

ClinPred

0.36

GERP RS

5.4

Varity_R

0.21

gMVP

0.14

Mutation Taster

=83/17

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

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NM_139318.5:c.2890C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over