Genetic Variant NM_139318.5:c.2942C>A (chr14-62707533-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.2942C>A(p.Ser981Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000153 in 1,308,966 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S981F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

KCNH5
NM_139318.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.63

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29935122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5 link	c.2942C>A	p.Ser981Tyr	missense_variant	Exon 11 of 11	ENST00000322893.12	NP_647479.2	Q8NCM2-1
KCNH5	NM_172375.3 link	c.*909C>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.2942C>A	p.Ser981Tyr	missense_variant	Exon 11 of 11	1	NM_139318.5	ENSP00000321427.7		Q8NCM2-1
KCNH5	ENST00000420622.6 link	c.*909C>A		downstream_gene_variant		1		ENSP00000395439.2		Q8NCM2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000589

AC:

AN:

169822

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000545

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000153

AC:

AN:

1308966

Hom.:

Cov.:

AF XY:

0.00000157

AC XY:

AN XY:

635692

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29522

American (AMR)

AF:

0.0000381

AC:

AN:

26230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18934

East Asian (EAS)

AF:

0.00

AC:

AN:

37680

South Asian (SAS)

AF:

0.0000183

AC:

AN:

54602

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1035436

Other (OTH)

AF:

0.00

AC:

AN:

53778

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000845

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.30

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.5

PhyloP100

3.6

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.012

Polyphen

0.90

Vest4

0.34

MutPred

0.21

Loss of relative solvent accessibility (P = 0.0186);

MVP

0.71

MPC

0.28

ClinPred

0.45

GERP RS

5.4

Varity_R

0.46

gMVP

0.46

Mutation Taster

=50/50

(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.2942C>A

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