NM_144633.3:c.490C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_144633.3(KCNH8):​c.490C>G​(p.Arg164Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R164Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

KCNH8
NM_144633.3 missense

Scores

10
7
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.81
Variant links:
Genes affected
KCNH8 (HGNC:18864): (potassium voltage-gated channel subfamily H member 8) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNH8NM_144633.3 linkc.490C>G p.Arg164Gly missense_variant Exon 4 of 16 ENST00000328405.7 NP_653234.2 Q96L42-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNH8ENST00000328405.7 linkc.490C>G p.Arg164Gly missense_variant Exon 4 of 16 1 NM_144633.3 ENSP00000328813.2 Q96L42-1
KCNH8ENST00000452398.5 linkn.490C>G non_coding_transcript_exon_variant Exon 4 of 16 1 ENSP00000412141.1 F8WCG6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458696
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
725754
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.36
T
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.82
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-5.8
D
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.80
MutPred
0.40
Gain of glycosylation at S167 (P = 0.0197);
MVP
0.95
MPC
0.26
ClinPred
0.99
D
GERP RS
4.9
Varity_R
0.53
gMVP
0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-19384126; API