rs140359227

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004137.4(KCNMB1):​c.136G>T​(p.Val46Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V46M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNMB1
NM_004137.4 missense, splice_region

Scores

2
17
Splicing: ADA: 0.0003730
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.00
Variant links:
Genes affected
KCNMB1 (HGNC:6285): (potassium calcium-activated channel subfamily M regulatory beta subunit 1) MaxiK channels are large conductance, voltage and calcium-sensitive potassium channels which are fundamental to the control of smooth muscle tone and neuronal excitability. MaxiK channels can be formed by 2 subunits: the pore-forming alpha subunit and the product of this gene, the modulatory beta subunit. Intracellular calcium regulates the physical association between the alpha and beta subunits. [provided by RefSeq, Jul 2008]
KCNIP1 (HGNC:15521): (potassium voltage-gated channel interacting protein 1) This gene encodes a member of the family of cytosolic voltage-gated potassium (Kv) channel-interacting proteins (KCNIPs), which belong to the neuronal calcium sensor (NCS) family of the calcium binding EF-hand proteins. They associate with Kv4 alpha subunits to form native Kv4 channel complexes. The encoded protein may regulate rapidly inactivating (A-type) currents, and hence neuronal membrane excitability, in response to changes in the concentration of intracellular calcium. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.38784263).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNMB1NM_004137.4 linkc.136G>T p.Val46Leu missense_variant, splice_region_variant Exon 3 of 4 ENST00000274629.9 NP_004128.1 Q16558-1
KCNIP1NM_001034838.3 linkc.88+29885C>A intron_variant Intron 1 of 7 NP_001030010.1 Q9NZI2-4
KCNIP1XM_017009407.2 linkc.88+29885C>A intron_variant Intron 2 of 8 XP_016864896.1 Q9NZI2-4
KCNIP1XM_017009408.2 linkc.88+29885C>A intron_variant Intron 1 of 3 XP_016864897.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNMB1ENST00000274629.9 linkc.136G>T p.Val46Leu missense_variant, splice_region_variant Exon 3 of 4 1 NM_004137.4 ENSP00000274629.3 Q16558-1

Frequencies

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
18
DANN
Benign
0.97
DEOGEN2
Benign
0.079
T;.
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.11
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.76
T;T
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.39
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
2.0
M;M
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.11
Sift
Benign
0.078
T;T
Sift4G
Uncertain
0.030
D;D
Polyphen
0.48
P;B
Vest4
0.23
MutPred
0.79
Loss of catalytic residue at V46 (P = 0.0601);Loss of catalytic residue at V46 (P = 0.0601);
MVP
0.27
MPC
0.22
ClinPred
0.66
D
GERP RS
4.7
Varity_R
0.095
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00037
dbscSNV1_RF
Benign
0.23
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: rs140359227; hg19: chr5-169810853; API