Genetic Variant KCNH5:p.Pro962Thr (chr14-62707591-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_139318.5(KCNH5):c.2884C>A(p.Pro962Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. P962S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNH5
NM_139318.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.36

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33723497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5 link	c.2884C>A	p.Pro962Thr	missense_variant	Exon 11 of 11	ENST00000322893.12	NP_647479.2	Q8NCM2-1
KCNH5	NM_172375.3 link	c.*851C>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.2884C>A	p.Pro962Thr	missense_variant	Exon 11 of 11	1	NM_139318.5	ENSP00000321427.7		Q8NCM2-1
KCNH5	ENST00000420622.6 link	c.*851C>A		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000395439.2		Q8NCM2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000504

AC:

AN:

198396

AF XY:

0.00000955

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1382248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

677092

African (AFR)

AF:

0.00

AC:

AN:

31076

American (AMR)

AF:

0.00

AC:

AN:

35018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21280

East Asian (EAS)

AF:

0.00

AC:

AN:

38792

South Asian (SAS)

AF:

0.00

AC:

AN:

72304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5378

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070696

Other (OTH)

AF:

0.00

AC:

AN:

56932

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.34

MetaSVM

Pathogenic

0.81

MutationAssessor

Benign

0.69

PhyloP100

4.4

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.33

REVEL

Uncertain

0.49

Sift

Benign

0.12

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.29

MutPred

0.18

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

MVP

0.42

MPC

0.13

ClinPred

0.53

GERP RS

5.4

Varity_R

0.11

gMVP

0.35

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

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over