5-170378831-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004137.4(KCNMB1):​c.449G>A​(p.Arg150His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

KCNMB1
NM_004137.4 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.00
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22918802).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNMB1NM_004137.4 linkc.449G>A p.Arg150His missense_variant Exon 4 of 4 ENST00000274629.9 NP_004128.1 Q16558-1
KCNIP1NM_001034838.3 linkc.88+24867C>T intron_variant Intron 1 of 7 NP_001030010.1 Q9NZI2-4
KCNIP1XM_017009407.2 linkc.88+24867C>T intron_variant Intron 2 of 8 XP_016864896.1 Q9NZI2-4
KCNIP1XM_017009408.2 linkc.88+24867C>T 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.449G>A p.Arg150His missense_variant Exon 4 of 4 1 NM_004137.4 ENSP00000274629.3 Q16558-1
KCNIP1ENST00000377360.8 linkc.88+24867C>T intron_variant Intron 1 of 7 1 ENSP00000366577.4 Q9NZI2-4
KCNIP1ENST00000517344.1 linkn.88+24867C>T intron_variant Intron 1 of 3 3 ENSP00000431053.1 E5RJY5
KCNIP1ENST00000518527.1 linkn.478+24867C>T intron_variant Intron 1 of 1 4

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152182
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251332
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.0000206
AC XY:
15
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152300
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000494
AC:
6
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.449G>A (p.R150H) alteration is located in exon 4 (coding exon 3) of the KCNMB1 gene. This alteration results from a G to A substitution at nucleotide position 449, causing the arginine (R) at amino acid position 150 to be replaced by a histidine (H). 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
Benign
0.19
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Benign
0.63
D
LIST_S2
Benign
0.85
D
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.23
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.5
M
PrimateAI
Benign
0.40
T
PROVEAN
Uncertain
-2.9
D
REVEL
Benign
0.20
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0080
D
Polyphen
1.0
D
Vest4
0.42
MVP
0.19
MPC
0.61
ClinPred
0.79
D
GERP RS
4.4
Varity_R
0.21
gMVP
0.72

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: rs200287944; hg19: chr5-169805835; API