Genetic Variant KCNMB4:p.Arg207Cys (chr12-70430639-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014505.6(KCNMB4):c.619C>T(p.Arg207Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,456,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KCNMB4
NM_014505.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2458576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMB4	NM_014505.6 link	c.619C>T	p.Arg207Cys	missense_variant	Exon 3 of 3	ENST00000258111.5	NP_055320.4	Q86W47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNMB4	ENST00000258111.5 link	c.619C>T	p.Arg207Cys	missense_variant	Exon 3 of 3	1	NM_014505.6	ENSP00000258111.4	Q86W47
KCNMB4	ENST00000531884.1 link	n.*291C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2		ENSP00000431137.1	H0YC85
KCNMB4	ENST00000531884.1 link	n.*291C>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000431137.1	H0YC85

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245070

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132566

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1456508

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724636

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.619C>T (p.R207C) alteration is located in exon 1 (coding exon 1) of the KCNMB4 gene. This alteration results from a C to T substitution at nucleotide position 619, causing the arginine (R) at amino acid position 207 to be replaced by a cysteine (C). 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

0.33

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.015

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.6

REVEL

Benign

0.21

Sift

Uncertain

0.011

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.40

MutPred

0.33

Loss of MoRF binding (P = 0.001);

MVP

0.17

MPC

2.2

ClinPred

0.87

GERP RS

5.1

Varity_R

0.22

gMVP

0.68

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