Genetic Variant NM_139318.5:c.766G>C (chr14-62981048-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_139318.5(KCNH5):c.766G>C(p.Val256Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V256I) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNH5
NM_139318.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.11

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5 link	c.766G>C	p.Val256Leu	missense_variant	Exon 6 of 11	ENST00000322893.12	NP_647479.2	Q8NCM2-1
KCNH5	NM_172375.3 link	c.766G>C	p.Val256Leu	missense_variant	Exon 6 of 10		NP_758963.1	Q8NCM2-2
KCNH5	XM_047431275.1 link	c.766G>C	p.Val256Leu	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>C	p.Val256Leu	missense_variant	Exon 6 of 11	1	NM_139318.5	ENSP00000321427.7	Q8NCM2-1
KCNH5	ENST00000420622.6 link	c.766G>C	p.Val256Leu	missense_variant	Exon 6 of 10	1		ENSP00000395439.2	Q8NCM2-2
KCNH5	ENST00000394964.3 link	n.931G>C		non_coding_transcript_exon_variant	Exon 6 of 7	1
KCNH5	ENST00000394968.2 link	c.592G>C	p.Val198Leu	missense_variant	Exon 6 of 11	2		ENSP00000378419.1	Q8NCM2-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

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:

8.99e-7

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.766G>C (p.V256L) alteration is located in exon 6 (coding exon 6) of the KCNH5 gene. This alteration results from a G to C substitution at nucleotide position 766, causing the valine (V) at amino acid position 256 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.092

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

L;L;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Pathogenic

0.76

Sift

Benign

0.048

D;T;T

Sift4G

Benign

0.064

T;T;T

Polyphen

0.97

D;P;P

Vest4

0.73

MutPred

0.52

Gain of catalytic residue at D251 (P = 0.0028);Gain of catalytic residue at D251 (P = 0.0028);.;

MVP

0.92

MPC

1.4

ClinPred

0.99

GERP RS

5.5

Varity_R

0.53

gMVP

0.81

Mutation Taster

=36/64

disease causing

(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.766G>C

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