Variant 5-170378801-G-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_004137.4(KCNMB1):c.479C>G(p.Ser160Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNMB1
NM_004137.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

Variant links:

Genes affected

KCNMB1 (HGNC:6285): (potassium calcium-activated channel subfamily M regulatory beta subunit 1) 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 product of this gene, the modulatory beta subunit. Intracellular calcium regulates the physical association between the alpha and beta subunits. [provided by RefSeq, Jul 2008]

KCNMB1 links:

KCNIP1 (HGNC:15521): (potassium voltage-gated channel interacting protein 1) This gene encodes a member of the family of cytosolic voltage-gated potassium (Kv) channel-interacting proteins (KCNIPs), which belong to the neuronal calcium sensor (NCS) family of the calcium binding EF-hand proteins. They associate with Kv4 alpha subunits to form native Kv4 channel complexes. The encoded protein may regulate rapidly inactivating (A-type) currents, and hence neuronal membrane excitability, in response to changes in the concentration of intracellular calcium. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

KCNIP1 links:

KCNIP1 (HGNC:):

KCNIP1 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
KCNMB1	NM_004137.4 linkuse as main transcript	c.479C>G	p.Ser160Cys	missense_variant	4/4	ENST00000274629.9	NP_004128.1	Q16558-1
KCNIP1	NM_001034838.3 linkuse as main transcript	c.88+24837G>C		intron_variant			NP_001030010.1	Q9NZI2-4
KCNIP1	XM_017009407.2 linkuse as main transcript	c.88+24837G>C		intron_variant			XP_016864896.1	Q9NZI2-4
KCNIP1	XM_017009408.2 linkuse as main transcript	c.88+24837G>C		intron_variant			XP_016864897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNMB1	ENST00000274629.9 linkuse as main transcript	c.479C>G	p.Ser160Cys	missense_variant	4/4	1	NM_004137.4	ENSP00000274629.3	Q16558-1
KCNIP1	ENST00000377360.8 linkuse as main transcript	c.88+24837G>C		intron_variant		1		ENSP00000366577.4	Q9NZI2-4
KCNIP1	ENST00000517344.1 linkuse as main transcript	n.88+24837G>C		intron_variant		3		ENSP00000431053.1	E5RJY5
KCNIP1	ENST00000518527.1 linkuse as main transcript	n.478+24837G>C		intron_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Jan 03, 2022

The c.479C>G (p.S160C) alteration is located in exon 4 (coding exon 3) of the KCNMB1 gene. This alteration results from a C to G substitution at nucleotide position 479, causing the serine (S) at amino acid position 160 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

0.099

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.023

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.72

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.93

PrimateAI

Benign

0.40

PROVEAN

Benign

0.49

REVEL

Benign

0.17

Sift

Benign

0.31

Sift4G

Uncertain

0.045

Polyphen

1.0

Vest4

0.40

MutPred

0.81

Gain of sheet (P = 0.0827);

MVP

0.32

MPC

0.49

ClinPred

0.75

GERP RS

3.4

Varity_R

0.050

gMVP

0.58

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over