14-62981048-C-T

Variant names:

Variant summary

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

The NM_139318.5(KCNH5):c.766G>A(p.Val256Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,854 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. V256L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

KCNH5
NM_139318.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.11

Publications

2 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=0.24597675).

BP6

Variant 14-62981048-C-T is Benign according to our data. Variant chr14-62981048-C-T is described in ClinVar as [Benign]. Clinvar id is 461399.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5 link	c.766G>A	p.Val256Ile	missense_variant	Exon 6 of 11	ENST00000322893.12	NP_647479.2	Q8NCM2-1
KCNH5	NM_172375.3 link	c.766G>A	p.Val256Ile	missense_variant	Exon 6 of 10		NP_758963.1	Q8NCM2-2
KCNH5	XM_047431275.1 link	c.766G>A	p.Val256Ile	missense_variant	Exon 6 of 10		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNH5	ENST00000322893.12 link	c.766G>A	p.Val256Ile	missense_variant	Exon 6 of 11	1	NM_139318.5	ENSP00000321427.7	Q8NCM2-1
KCNH5	ENST00000420622.6 link	c.766G>A	p.Val256Ile	missense_variant	Exon 6 of 10	1		ENSP00000395439.2	Q8NCM2-2
KCNH5	ENST00000394964.3 link	n.931G>A		non_coding_transcript_exon_variant	Exon 6 of 7	1
KCNH5	ENST00000394968.2 link	c.592G>A	p.Val198Ile	missense_variant	Exon 6 of 11	2		ENSP00000378419.1	Q8NCM2-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251316

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1111996

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.0000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Benign:1

Feb 13, 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

0.14

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Benign

0.59

DEOGEN2

Uncertain

0.52

D;.;.

Eigen

Benign

0.023

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.062

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

0.75

N;N;.

PhyloP100

6.1

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.74

N;N;N

REVEL

Uncertain

0.61

Sift

Benign

0.67

T;T;T

Sift4G

Benign

0.58

T;T;T

Polyphen

0.84

P;B;B

Vest4

0.35

MutPred

0.51

Gain of catalytic residue at D251 (P = 0.0022);Gain of catalytic residue at D251 (P = 0.0022);.;

MVP

0.82

MPC

0.69

ClinPred

0.37

GERP RS

5.5

Varity_R

0.17

gMVP

0.51

Mutation Taster

=56/44

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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14-62981048-C-T

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