3-178842660-A-G

Position:

• chr3-178842660-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_181361.3(KCNMB2):​c.431A>G​(p.Tyr144Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNMB2 NM_181361.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.99

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMB2	NM_181361.3	c.431A>G	p.Tyr144Cys	missense_variant	5/5	ENST00000452583.6	NP_852006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMB2	ENST00000452583.6	c.431A>G	p.Tyr144Cys	missense_variant	5/5	1	NM_181361.3	ENSP00000397483.1
ENSG00000275163	ENST00000614557.1	c.431A>G	p.Tyr144Cys	missense_variant	5/5	2		ENSP00000483415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.431A>G (p.Y144C) alteration is located in exon 5 (coding exon 4) of the KCNMB2 gene. This alteration results from a A to G substitution at nucleotide position 431, causing the tyrosine (Y) at amino acid position 144 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;T;T;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;.;.;.;D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	M;M;M;M;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.1	D;D;D;D;.;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.89
MutPred		0.90		Gain of catalytic residue at K147 (P = 0.088);Gain of catalytic residue at K147 (P = 0.088);Gain of catalytic residue at K147 (P = 0.088);Gain of catalytic residue at K147 (P = 0.088);.;Gain of catalytic residue at K147 (P = 0.088);
MVP		0.59
MPC		1.1
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.85
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-178560448;