dbSNP rs770772310: KCNMB2:p.Ser76Arg (chr3-178828178-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_181361.3(KCNMB2):c.228C>G(p.Ser76Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 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. Synonymous variant affecting the same amino acid position (i.e. S76S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNMB2
NM_181361.3 missense, splice_region

Scores

Splicing: ADA: 0.00009226

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0710

Variant links:

Genes affected

KCNMB2 (HGNC:6286): (potassium calcium-activated channel subfamily M regulatory beta subunit 2) 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 modulatory beta subunit. The protein encoded by this gene is an auxiliary beta subunit which decreases the activation time of MaxiK alpha subunit currents. Alternative splicing results in multiple transcript variants of this gene. Additional variants are discussed in the literature, but their full length nature has not been described. [provided by RefSeq, Jul 2013]

KCNMB2 links:

ENSG00000275163 (HGNC:):

ENSG00000275163 links:

KCNMB2-AS1 (HGNC:51409): (KCNMB2 antisense RNA 1)

KCNMB2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMB2	NM_181361.3 link	c.228C>G	p.Ser76Arg	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000452583.6	NP_852006.1	Q9Y691B5BNW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMB2	ENST00000452583.6 link	c.228C>G	p.Ser76Arg	missense_variant, splice_region_variant	Exon 4 of 5	1	NM_181361.3	ENSP00000397483.1		Q9Y691
ENSG00000275163	ENST00000614557.1 link	c.228C>G	p.Ser76Arg	missense_variant, splice_region_variant	Exon 4 of 5	2		ENSP00000483415.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248900

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134578

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458920

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725778

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.14

.;T;T;T;.;T;.;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.74

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

D;.;.;.;D;.;D;D

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

.;L;L;L;.;L;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.8

D;D;D;D;D;D;.;.

REVEL

Benign

0.27

Sift

Benign

0.034

D;D;D;D;D;D;.;.

Sift4G

Uncertain

0.037

D;D;D;D;T;D;D;D

Polyphen

0.026

.;B;B;B;.;B;.;.

Vest4

0.71, 0.68

MutPred

0.86

Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);.;Gain of solvent accessibility (P = 0.1185);

MVP

0.28

MPC

0.35

ClinPred

0.14

GERP RS

-2.6

Varity_R

0.62

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000092

dbscSNV1_RF

Benign

0.17

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over