3-19438173-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000328405.7(KCNH8):​c.1187A>G​(p.His396Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

KCNH8
ENST00000328405.7 missense

Scores

4
10
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH8NM_144633.3 linkuse as main transcriptc.1187A>G p.His396Arg missense_variant 8/16 ENST00000328405.7 NP_653234.2
LOC105376982XR_940640.3 linkuse as main transcriptn.2617-37526T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH8ENST00000328405.7 linkuse as main transcriptc.1187A>G p.His396Arg missense_variant 8/161 NM_144633.3 ENSP00000328813 P1Q96L42-1
KCNH8ENST00000452398.5 linkuse as main transcriptc.*682A>G 3_prime_UTR_variant, NMD_transcript_variant 9/161 ENSP00000412141
ENST00000670571.1 linkuse as main transcriptn.654+32182T>C intron_variant, non_coding_transcript_variant
ENST00000668274.1 linkuse as main transcriptn.353-37526T>C intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 23, 2024The c.1187A>G (p.H396R) alteration is located in exon 8 (coding exon 8) of the KCNH8 gene. This alteration results from a A to G substitution at nucleotide position 1187, causing the histidine (H) at amino acid position 396 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.070
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D
Eigen
Benign
-0.055
Eigen_PC
Benign
0.092
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
T
M_CAP
Uncertain
0.28
D
MetaRNN
Uncertain
0.58
D
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Benign
1.7
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-5.5
D
REVEL
Uncertain
0.61
Sift
Uncertain
0.0090
D
Sift4G
Uncertain
0.021
D
Polyphen
0.0040
B
Vest4
0.56
MutPred
0.63
Gain of MoRF binding (P = 0.0113);
MVP
0.87
MPC
1.8
ClinPred
0.98
D
GERP RS
3.3
Varity_R
0.53
gMVP
0.95

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: chr3-19479665; API