Variant 12-70366757-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMB4	NM_014505.6 linkuse as main transcript	c.23A>C	p.Tyr8Ser	missense_variant	1/3	ENST00000258111.5	NP_055320.4	Q86W47
KCNMB4	XM_011538188.3 linkuse as main transcript	c.23A>C	p.Tyr8Ser	missense_variant	1/3		XP_011536490.1
KCNMB4	XM_047428701.1 linkuse as main transcript	c.23A>C	p.Tyr8Ser	missense_variant	1/3		XP_047284657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMB4	ENST00000258111.5 linkuse as main transcript	c.23A>C	p.Tyr8Ser	missense_variant	1/3	1	NM_014505.6	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

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151722

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74060

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000674

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.23A>C (p.Y8S) alteration is located in exon 1 (coding exon 1) of the KCNMB4 gene. This alteration results from a A to C substitution at nucleotide position 23, causing the tyrosine (Y) at amino acid position 8 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

0.19

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

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

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

Varity_R

0.43

gMVP

0.93

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over