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GeneBe

3-19450261-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_144633.3(KCNH8):c.1531T>G(p.Phe511Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,512 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 (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNH8
NM_144633.3 missense

Scores

11
7
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.99
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNH8NM_144633.3 linkuse as main transcriptc.1531T>G p.Phe511Val missense_variant 9/16 ENST00000328405.7
LOC105376982XR_940640.3 linkuse as main transcriptn.2616+34090A>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNH8ENST00000328405.7 linkuse as main transcriptc.1531T>G p.Phe511Val missense_variant 9/161 NM_144633.3 P1Q96L42-1
KCNH8ENST00000452398.5 linkuse as main transcriptc.*1026T>G 3_prime_UTR_variant, NMD_transcript_variant 10/161
ENST00000670571.1 linkuse as main transcriptn.654+20094A>C intron_variant, non_coding_transcript_variant
ENST00000668274.1 linkuse as main transcriptn.352+34090A>C intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251156
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135738
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000869
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:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461512
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727060
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

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 GeneticsMar 11, 2022The c.1531T>G (p.F511V) alteration is located in exon 9 (coding exon 9) of the KCNH8 gene. This alteration results from a T to G substitution at nucleotide position 1531, causing the phenylalanine (F) at amino acid position 511 to be replaced by a valine (V). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.50
Cadd
Pathogenic
30
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.48
T
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.87
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-6.3
D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.014
D
Sift4G
Uncertain
0.040
D
Polyphen
1.0
D
Vest4
0.88
MutPred
0.43
Gain of loop (P = 0.0312);
MVP
0.96
MPC
2.0
ClinPred
0.94
D
GERP RS
6.2
Varity_R
0.45
gMVP
0.89

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.

Other links and lift over

dbSNP: rs1431425788; hg19: chr3-19491753; API