12-70366757-A-G

Variant names:

• chr12-70366757-A-G
• rs1414173995
• NM_014505.6:c.23A>G

Variant summary

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

The NM_014505.6(KCNMB4):​c.23A>G​(p.Tyr8Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,076 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. Y8S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNMB4 NM_014505.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.60
• Publications: 0 publications found

Genes affected

KCNMB4 (HGNC:6289): (potassium calcium-activated channel subfamily M regulatory beta subunit 4) 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 slows activation kinetics, leads to steeper calcium sensitivity, and shifts the voltage range of current activation to more negative potentials than does the beta 1 subunit. [provided by RefSeq, Jul 2008]

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_014505.6. 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
	KCNMB4	NM_014505.6	MANE Select	c.23A>G	p.Tyr8Cys	missense	Exon 1 of 3	NP_055320.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMB4	ENST00000258111.5	TSL:1 MANE Select	c.23A>G	p.Tyr8Cys	missense	Exon 1 of 3	ENSP00000258111.4	Q86W47

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453076 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722754

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.00 AC: 0 AN: 85584

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 49130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109552

Other (OTH) AF: 0.00 AC: 0 AN: 60138

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.23
Sift	Benign	0.039	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.56		Gain of catalytic residue at E9 (P = 0.0024)
MVP		0.21
MPC		2.0
ClinPred		0.97	D
GERP RS		3.0
PromoterAI		0.016	Neutral
Varity_R		0.34
gMVP		0.95
Mutation Taster		=65/35	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: rs1414173995; hg19: chr12-70760537;