rs745970423

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate

The NM_139318.5(KCNH5):c.460C>T(p.Arg154Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R154R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

KCNH5
NM_139318.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.87

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP2

Missense variant where missense usually causes diseases, KCNH5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNH5	NM_139318.5 linkuse as main transcript	c.460C>T	p.Arg154Trp	missense_variant	5/11	ENST00000322893.12
KCNH5	NM_172375.3 linkuse as main transcript	c.460C>T	p.Arg154Trp	missense_variant	5/10
KCNH5	XM_047431275.1 linkuse as main transcript	c.460C>T	p.Arg154Trp	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH5	ENST00000322893.12 linkuse as main transcript	c.460C>T	p.Arg154Trp	missense_variant	5/11	1	NM_139318.5	P1	Q8NCM2-1
KCNH5	ENST00000420622.6 linkuse as main transcript	c.460C>T	p.Arg154Trp	missense_variant	5/10	1			Q8NCM2-2
KCNH5	ENST00000394964.3 linkuse as main transcript	n.625C>T		non_coding_transcript_exon_variant	5/7	1
KCNH5	ENST00000394968.2 linkuse as main transcript	c.286C>T	p.Arg96Trp	missense_variant	5/11	2			Q8NCM2-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251096

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135694

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461186

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 07, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KCNH5-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 154 of the KCNH5 protein (p.Arg154Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.063

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.3

D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.85

MutPred

0.53

Gain of catalytic residue at L152 (P = 0.0011);Gain of catalytic residue at L152 (P = 0.0011);.;

MVP

0.97

MPC

1.7

ClinPred

0.81

GERP RS

2.8

Varity_R

0.73

gMVP

0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over