chr8-72936729-C-A

Variant summary

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

The NM_004770.3(KCNB2):​c.1374C>A​(p.Phe458Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F458F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNB2
NM_004770.3 missense

Scores

10
4
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0960
Variant links:
Genes affected
KCNB2 (HGNC:6232): (potassium voltage-gated channel subfamily B member 2) 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. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shab-related subfamily. This member is a delayed rectifier potassium channel. The gene is expressed in gastrointestinal smooth muscle cells. [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, 0.862

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNB2NM_004770.3 linkc.1374C>A p.Phe458Leu missense_variant Exon 3 of 3 ENST00000523207.2 NP_004761.2 Q92953
KCNB2XM_017013982.2 linkc.639C>A p.Phe213Leu missense_variant Exon 2 of 2 XP_016869471.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNB2ENST00000523207.2 linkc.1374C>A p.Phe458Leu missense_variant Exon 3 of 3 1 NM_004770.3 ENSP00000430846.1 Q92953

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461870
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727242
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:
8.99e-7
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
0.99
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Benign
0.40
T
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.86
D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Uncertain
2.2
M
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.4
D
REVEL
Pathogenic
0.67
Sift
Benign
0.045
D
Sift4G
Uncertain
0.010
D
Polyphen
1.0
D
Vest4
0.88
MutPred
0.40
Gain of ubiquitination at K455 (P = 0.0469);
MVP
0.93
MPC
1.5
ClinPred
1.0
D
GERP RS
-6.5
Varity_R
0.28
gMVP
0.91

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: chr8-73848964; API