NM_181361.3:c.166G>A

Variant names:

• chr3-178825697-G-A
• rs776702750
• NM_181361.3:c.166G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181361.3(KCNMB2):​c.166G>A​(p.Val56Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V56L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNMB2 NM_181361.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.64
• Publications: 0 publications found

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:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181361.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMB2	NM_181361.3	MANE Select	c.166G>A	p.Val56Met	missense	Exon 3 of 5	NP_852006.1	Q9Y691
	KCNMB2	NM_001278911.2		c.166G>A	p.Val56Met	missense	Exon 3 of 5	NP_001265840.1	Q9Y691
	KCNMB2	NM_005832.5		c.166G>A	p.Val56Met	missense	Exon 4 of 6	NP_005823.1	Q9Y691

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMB2	ENST00000452583.6	TSL:1 MANE Select	c.166G>A	p.Val56Met	missense	Exon 3 of 5	ENSP00000397483.1	Q9Y691
	KCNMB2	ENST00000358316.7	TSL:1	c.166G>A	p.Val56Met	missense	Exon 2 of 4	ENSP00000351068.3	Q9Y691
	KCNMB2	ENST00000432997.5	TSL:1	c.166G>A	p.Val56Met	missense	Exon 3 of 5	ENSP00000407592.1	Q9Y691

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251358 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461766 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727190

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111898

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Benign	0.22	T
Sift4G	Benign	0.22	T
Polyphen		0.97	D
Vest4		0.55
MutPred		0.65		Loss of catalytic residue at V56 (P = 0.0248)
MVP		0.043
MPC		1.0
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.075
gMVP		0.56
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs776702750; hg19: chr3-178543485; COSMIC: COSV106106141; COSMIC: COSV106106141;