5-170378862-G-A

Position:

chr5-170378862-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_004137.4(KCNMB1):c.418C>T(p.Arg140Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,614,238 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.020 ( 96 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 97 hom. )

Consequence

KCNMB1
NM_004137.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.16

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027773976).

BP6

Variant 5-170378862-G-A is Benign according to our data. Variant chr5-170378862-G-A is described in ClinVar as [Benign]. Clinvar id is 3049582.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMB1	NM_004137.4 linkuse as main transcript	c.418C>T	p.Arg140Trp	missense_variant	4/4	ENST00000274629.9	NP_004128.1	Q16558-1
KCNIP1	NM_001034838.3 linkuse as main transcript	c.88+24898G>A		intron_variant			NP_001030010.1	Q9NZI2-4
KCNIP1	XM_017009407.2 linkuse as main transcript	c.88+24898G>A		intron_variant			XP_016864896.1	Q9NZI2-4
KCNIP1	XM_017009408.2 linkuse as main transcript	c.88+24898G>A		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.418C>T	p.Arg140Trp	missense_variant	4/4	1	NM_004137.4	ENSP00000274629.3	Q16558-1
KCNIP1	ENST00000377360.8 linkuse as main transcript	c.88+24898G>A		intron_variant		1		ENSP00000366577.4	Q9NZI2-4
KCNIP1	ENST00000517344.1 linkuse as main transcript	n.88+24898G>A		intron_variant		3		ENSP00000431053.1	E5RJY5
KCNIP1	ENST00000518527.1 linkuse as main transcript	n.478+24898G>A		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0202

AC:

3076

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0704

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00673

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00540

AC:

1358

AN:

251352

Hom.:

AF XY:

0.00407

AC XY:

553

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0727

Gnomad AMR exome

AF:

0.00321

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00215

AC:

3138

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

1356

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0739

Gnomad4 AMR exome

AF:

0.00360

Gnomad4 ASJ exome

AF:

0.000880

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000159

Gnomad4 OTH exome

AF:

0.00440

GnomAD4 genome

AF:

0.0203

AC:

3092

AN:

152356

Hom.:

Cov.:

AF XY:

0.0188

AC XY:

1404

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.0706

Gnomad4 AMR

AF:

0.00673

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00427

Hom.:

Bravo

AF:

0.0229

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0747

AC:

329

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00672

AC:

816

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KCNMB1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.10

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.016

Polyphen

0.99

Vest4

0.21

MVP

0.47

MPC

0.45

ClinPred

0.013

GERP RS

4.4

Varity_R

0.073

gMVP

0.38

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

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