rs2301149

Variant names:

• chr5-170378952-C-G
• rs2301149
• NM_004137.4:c.328G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-170378952-C-G
• chr5-170378952-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 26 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 -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	c.328G>C	p.Val110Leu	missense_variant	Exon 4 of 4	ENST00000274629.9	NP_004128.1
KCNIP1	NM_001034838.3	c.88+24988C>G		intron_variant	Intron 1 of 7		NP_001030010.1
KCNIP1	XM_017009407.2	c.88+24988C>G		intron_variant	Intron 2 of 8		XP_016864896.1
KCNIP1	XM_017009408.2	c.88+24988C>G		intron_variant	Intron 1 of 3		XP_016864897.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0987 AC: 15016 AN: 152188 Hom.: 791 Cov.: 33

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

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.: 33 AF XY: 0.0889 AC XY: 64638 AN XY: 727064

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

GnomAD4 genome AF: 0.0987 AC: 15035 AN: 152306 Hom.: 792 Cov.: 33 AF XY: 0.0993 AC XY: 7391 AN XY: 74466

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: 63 AN: 294

European-Non Finnish (NFE) AF: 0.0857 AC: 5829 AN: 68028

Other (OTH) AF: 0.113 AC: 239 AN: 2116

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	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.1	N
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.078
Sift	Benign	0.32	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.015
MutPred		0.074		Gain of loop (P = 0.2045);
MPC		0.11
ClinPred		0.0021	T
GERP RS		3.0
Varity_R		0.035
gMVP		0.17
Mutation Taster		=98/2	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: rs2301149; hg19: chr5-169805956; COSMIC: COSV51131306; COSMIC: COSV51131306;