Genetic Variant KCNH5:p.Pro976Arg (chr14-62707548-G-C) – 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.2927C>G(p.Pro976Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000744 in 1,343,774 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P976L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

KCNH5
NM_139318.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.12

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:

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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.2927C>G	p.Pro976Arg	missense_variant	Exon 11 of 11	ENST00000322893.12	NP_647479.2	Q8NCM2-1
KCNH5	NM_172375.3 link	c.*894C>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.2927C>G	p.Pro976Arg	missense_variant	Exon 11 of 11	1	NM_139318.5	ENSP00000321427.7		Q8NCM2-1
KCNH5	ENST00000420622.6 link	c.*894C>G		downstream_gene_variant		1		ENSP00000395439.2		Q8NCM2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.44e-7

AC:

AN:

1343774

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

655062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30006

American (AMR)

AF:

0.00

AC:

AN:

28112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19582

East Asian (EAS)

AF:

0.0000260

AC:

AN:

38412

South Asian (SAS)

AF:

0.00

AC:

AN:

63002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5262

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1054826

Other (OTH)

AF:

0.00

AC:

AN:

55348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.70

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

PhyloP100

8.1

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.62

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

0.99

Vest4

0.69

MutPred

0.15

Loss of glycosylation at P976 (P = 0.0289);

MVP

0.80

MPC

0.32

ClinPred

0.98

GERP RS

5.4

Varity_R

0.48

gMVP

0.59

Mutation Taster

=67/33

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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14-62707548-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over