chr5-170378952-C-G

Position:

• chr5-170378952-C-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
KCNMB1	NM_004137.4	c.328G>C	p.Val110Leu	missense_variant	4/4	ENST00000274629.9
KCNIP1	NM_001034838.3	c.88+24988C>G		intron_variant
KCNIP1	XM_017009407.2	c.88+24988C>G		intron_variant
KCNIP1	XM_017009408.2	c.88+24988C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMB1	ENST00000274629.9	c.328G>C	p.Val110Leu	missense_variant	4/4	1	NM_004137.4	P1
KCNIP1	ENST00000377360.8	c.88+24988C>G		intron_variant		1		P4
KCNIP1	ENST00000517344.1	c.88+24988C>G		intron_variant, NMD_transcript_variant		3
KCNIP1	ENST00000518527.1	n.478+24988C>G		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.105 AC: 26075 AN: 249430 Hom.: 1554 AF XY: 0.103 AC XY: 13957 AN XY: 134968

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 SAS exome AF: 0.120

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

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.0594

Gnomad4 NFE exome AF: 0.0790

Gnomad4 OTH exome AF: 0.102

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

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.0602

Gnomad4 NFE AF: 0.0857

Gnomad4 OTH AF: 0.113

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
MutationTaster	Benign	6.4e-9	P;P
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

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

Other links and lift over

dbSNP: rs2301149; hg19: chr5-169805956; COSMIC: COSV51131306; COSMIC: COSV51131306;