3-178842681-A-G

Position:

• chr3-178842681-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181361.3(KCNMB2):​c.452A>G​(p.Asn151Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KCNMB2 NM_181361.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12500456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMB2	NM_181361.3	c.452A>G	p.Asn151Ser	missense_variant	5/5	ENST00000452583.6	NP_852006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMB2	ENST00000452583.6	c.452A>G	p.Asn151Ser	missense_variant	5/5	1	NM_181361.3	ENSP00000397483.1
ENSG00000275163	ENST00000614557.1	c.452A>G	p.Asn151Ser	missense_variant	5/5	2		ENSP00000483415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460184 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726484

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Nov 24, 2024

The c.452A>G (p.N151S) alteration is located in exon 5 (coding exon 4) of the KCNMB2 gene. This alteration results from a A to G substitution at nucleotide position 452, causing the asparagine (N) at amino acid position 151 to be replaced by a serine (S). 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	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T;T;T;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0075
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	.;.;.;.;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;L;L;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N;N;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.042	D;D;D;D;.;.
Sift4G	Benign	0.089	T;T;T;T;T;T
Polyphen		0.011	B;B;B;B;.;.
Vest4		0.083
MutPred		0.63		Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);.;Gain of disorder (P = 0.0621);
MVP		0.13
MPC		0.26
ClinPred		0.73	D
GERP RS		3.7
Varity_R		0.096
gMVP		0.54

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: chr3-178560469;