chr5-170378862-G-A

Variant names:

• chr5-170378862-G-A
• rs76348543
• NM_004137.4:c.418C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R140Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (96 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (97 hom.)
• Consequence: KCNMB1 NM_004137.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.16
• Publications: 7 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004137.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMB1	NM_004137.4	MANE Select	c.418C>T	p.Arg140Trp	missense	Exon 4 of 4	NP_004128.1	Q16558-1
	KCNIP1	NM_001034838.3		c.88+24898G>A		intron	N/A	NP_001030010.1	Q9NZI2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMB1	ENST00000274629.9	TSL:1 MANE Select	c.418C>T	p.Arg140Trp	missense	Exon 4 of 4	ENSP00000274629.3	Q16558-1
	KCNIP1	ENST00000377360.8	TSL:1	c.88+24898G>A		intron	N/A	ENSP00000366577.4	Q9NZI2-4
	KCNMB1	ENST00000962422.1		c.418C>T	p.Arg140Trp	missense	Exon 4 of 4	ENSP00000632481.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3076 AN: 152238 Hom.: 95 Cov.: 33

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

GnomAD2 exomes AF: 0.00540 AC: 1358 AN: 251352 AF XY: 0.00407

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 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.: 97 Cov.: 32 AF XY: 0.00186 AC XY: 1356 AN XY: 727244

African (AFR) AF: 0.0739 AC: 2473 AN: 33476

American (AMR) AF: 0.00360 AC: 161 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000159 AC: 177 AN: 1112012

Other (OTH) AF: 0.00440 AC: 266 AN: 60394

GnomAD4 genome AF: 0.0203 AC: 3092 AN: 152356 Hom.: 96 Cov.: 33 AF XY: 0.0188 AC XY: 1404 AN XY: 74510

African (AFR) AF: 0.0706 AC: 2934 AN: 41578

American (AMR) AF: 0.00673 AC: 103 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68032

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.00822 Hom.: 78

Bravo AF: 0.0229

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0747 AC: 329

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00672 AC: 816

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KCNMB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.2
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.21
MVP		0.47
MPC		0.45
ClinPred		0.013	T
GERP RS		4.4
Varity_R		0.073
gMVP		0.38
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs76348543; hg19: chr5-169805866;