5-170378952-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004137.4(KCNMB1):c.328G>C(p.Val110Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0886 in 1,613,818 control chromosomes in the GnomAD database, including 7,100 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.099 ( 792 hom., cov: 33)

Exomes 𝑓: 0.088 ( 6308 hom. )

Consequence

KCNMB1
NM_004137.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.31

Publications

26 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015092194).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMB1	NM_004137.4 link	c.328G>C	p.Val110Leu	missense_variant	Exon 4 of 4	ENST00000274629.9	NP_004128.1	Q16558-1
KCNIP1	NM_001034838.3 link	c.88+24988C>G		intron_variant	Intron 1 of 7		NP_001030010.1	Q9NZI2-4
KCNIP1	XM_017009407.2 link	c.88+24988C>G		intron_variant	Intron 2 of 8		XP_016864896.1	Q9NZI2-4
KCNIP1	XM_017009408.2 link	c.88+24988C>G		intron_variant	Intron 1 of 3		XP_016864897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNMB1	ENST00000274629.9 link	c.328G>C	p.Val110Leu	missense_variant	Exon 4 of 4	1	NM_004137.4	ENSP00000274629.3	Q16558-1
KCNIP1	ENST00000377360.8 link	c.88+24988C>G		intron_variant	Intron 1 of 7	1		ENSP00000366577.4	Q9NZI2-4
KCNIP1	ENST00000517344.1 link	n.88+24988C>G		intron_variant	Intron 1 of 3	3		ENSP00000431053.1	E5RJY5
KCNIP1	ENST00000518527.1 link	n.478+24988C>G		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes

AF:

0.0987

AC:

15016

AN:

152188

Hom.:

791

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.145

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.130

Gnomad FIN

AF:

0.0602

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.0857

Gnomad OTH

AF:

0.114

GnomAD2 exomes

AF:

0.105

AC:

26075

AN:

249430

AF XY:

0.103

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.143

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.128

Gnomad FIN exome

AF:

0.0605

Gnomad NFE exome

AF:

0.0875

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.0876

AC:

127995

AN:

1461512

Hom.:

6308

Cov.:

AF XY:

0.0889

AC XY:

64638

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.117

AC:

3919

AN:

33468

American (AMR)

AF:

0.141

AC:

6295

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

3882

AN:

26124

East Asian (EAS)

AF:

0.133

AC:

5289

AN:

39692

South Asian (SAS)

AF:

0.119

AC:

10261

AN:

86238

European-Finnish (FIN)

AF:

0.0594

AC:

3171

AN:

53412

Middle Eastern (MID)

AF:

0.218

AC:

1256

AN:

5764

European-Non Finnish (NFE)

AF:

0.0790

AC:

87784

AN:

1111738

Other (OTH)

AF:

0.102

AC:

6138

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

5959

11918

17877

23836

29795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3286

6572

9858

13144

16430

<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:

0.0987

AC:

15035

AN:

152306

Hom.:

792

Cov.:

AF XY:

0.0993

AC XY:

7391

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.110

AC:

4577

AN:

41566

American (AMR)

AF:

0.123

AC:

1885

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

504

AN:

3470

East Asian (EAS)

AF:

0.126

AC:

649

AN:

5170

South Asian (SAS)

AF:

0.131

AC:

631

AN:

4830

European-Finnish (FIN)

AF:

0.0602

AC:

639

AN:

10618

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0857

AC:

5829

AN:

68028

Other (OTH)

AF:

0.113

AC:

239

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

716

1433

2149

2866

3582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0876

Hom.:

506

Bravo

AF:

0.103

TwinsUK

AF:

0.0801

AC:

297

ALSPAC

AF:

0.0771

AC:

297

ESP6500AA

AF:

0.106

AC:

466

ESP6500EA

AF:

0.0843

AC:

725

ExAC

AF:

0.103

AC:

12458

EpiCase

AF:

0.0918

EpiControl

AF:

0.0971

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.024

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.25

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.1

PhyloP100

1.3

PrimateAI

Benign

0.40

PROVEAN

Benign

0.16

REVEL

Benign

0.078

Sift

Benign

0.32

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.015

MutPred

0.074

Gain of loop (P = 0.2045);

MPC

0.11

ClinPred

0.0021

GERP RS

3.0

Varity_R

0.035

gMVP

0.17

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over