Genetic Variant NM_014505.6:c.23A>C (chr12-70366757-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014505.6(KCNMB4):c.23A>C(p.Tyr8Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,604,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNMB4
NM_014505.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.60

Publications

0 publications found

Variant links:

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]

KCNMB4 links:

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ACMG classification

Classification was made for transcript

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>C	p.Tyr8Ser	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>C	p.Tyr8Ser	missense	Exon 1 of 3	ENSP00000258111.4	Q86W47

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151722

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453076

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722754

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33380

American (AMR)

AF:

0.00

AC:

AN:

44214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39462

South Asian (SAS)

AF:

0.00

AC:

AN:

85584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109552

Other (OTH)

AF:

0.00

AC:

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151722

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41382

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5074

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67906

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000674

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

7.6

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.11

REVEL

Benign

0.20

Sift

Benign

0.44

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.69

MVP

0.26

MPC

1.6

ClinPred

0.94

GERP RS

3.0

PromoterAI

0.085

Neutral

(source)

Varity_R

0.43

gMVP

0.93

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over