3-178825709-A-G

Position:

• chr3-178825709-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181361.3(KCNMB2):​c.178A>G​(p.Met60Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNMB2 NM_181361.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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]

ENSG00000275163 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMB2	NM_181361.3	c.178A>G	p.Met60Val	missense_variant	3/5	ENST00000452583.6	NP_852006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMB2	ENST00000452583.6	c.178A>G	p.Met60Val	missense_variant	3/5	1	NM_181361.3	ENSP00000397483.1
ENSG00000275163	ENST00000614557.1	c.178A>G	p.Met60Val	missense_variant	3/5	2		ENSP00000483415.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2024

The c.178A>G (p.M60V) alteration is located in exon 3 (coding exon 2) of the KCNMB2 gene. This alteration results from a A to G substitution at nucleotide position 178, causing the methionine (M) at amino acid position 60 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	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	.;T;T;T;.;T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;.;.;.;T;.;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;L;L;.;L;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;.;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.024	D;D;D;D;D;D;.;.
Sift4G	Uncertain	0.019	D;T;T;T;D;T;T;T
Polyphen		0.98	.;D;D;D;.;D;.;.
Vest4		0.95, 0.92
MutPred		0.63		Gain of catalytic residue at M60 (P = 0.0396);Gain of catalytic residue at M60 (P = 0.0396);Gain of catalytic residue at M60 (P = 0.0396);Gain of catalytic residue at M60 (P = 0.0396);Gain of catalytic residue at M60 (P = 0.0396);Gain of catalytic residue at M60 (P = 0.0396);.;Gain of catalytic residue at M60 (P = 0.0396);
MVP		0.33
MPC		0.98
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.49
gMVP		0.76

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: chr3-178543497;