3-178825742-C-T

Variant names:

• chr3-178825742-C-T
• rs550065789
• NM_181361.3:c.211C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_181361.3(KCNMB2):​c.211C>T​(p.Arg71Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,612,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R71S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KCNMB2 NM_181361.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75
• Publications: 1 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

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.211C>T	p.Arg71Cys	missense	Exon 3 of 5	NP_852006.1	Q9Y691
	KCNMB2	NM_001278911.2		c.211C>T	p.Arg71Cys	missense	Exon 3 of 5	NP_001265840.1	Q9Y691
	KCNMB2	NM_005832.5		c.211C>T	p.Arg71Cys	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.211C>T	p.Arg71Cys	missense	Exon 3 of 5	ENSP00000397483.1	Q9Y691
	KCNMB2	ENST00000358316.7	TSL:1	c.211C>T	p.Arg71Cys	missense	Exon 2 of 4	ENSP00000351068.3	Q9Y691
	KCNMB2	ENST00000432997.5	TSL:1	c.211C>T	p.Arg71Cys	missense	Exon 3 of 5	ENSP00000407592.1	Q9Y691

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152048 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250976 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1460712 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726516

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111086

Other (OTH) AF: 0.0000166 AC: 1 AN: 60326

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

African (AFR) AF: 0.0000482 AC: 2 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.66		Loss of helix (P = 0.2271)
MVP		0.47
MPC		1.1
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.51
gMVP		0.80
Mutation Taster		=39/61	disease causing

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: rs550065789; hg19: chr3-178543530; COSMIC: COSV64201500; COSMIC: COSV64201500;