5-170383849-C-G

Variant names:

• chr5-170383849-C-G
• rs140359227
• NM_004137.4:c.136G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004137.4(KCNMB1):​c.136G>C​(p.Val46Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V46M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNMB1 NM_004137.4 missense, splice_region
• Scores: Splicing: ADA: 0.002266
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38826883).

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.136G>C	p.Val46Leu	missense splice_region	Exon 3 of 4	NP_004128.1	Q16558-1
	KCNIP1	NM_001034838.3		c.88+29885C>G		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.136G>C	p.Val46Leu	missense splice_region	Exon 3 of 4	ENSP00000274629.3	Q16558-1
	KCNIP1	ENST00000377360.8	TSL:1	c.88+29885C>G		intron	N/A	ENSP00000366577.4	Q9NZI2-4
	KCNMB1	ENST00000962422.1		c.136G>C	p.Val46Leu	missense splice_region	Exon 3 of 4	ENSP00000632481.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.078	T
Sift4G	Uncertain	0.030	D
Polyphen		0.48	P
Vest4		0.23
MutPred		0.79		Loss of catalytic residue at V46 (P = 0.0601)
MVP		0.27
MPC		0.22
ClinPred		0.51	D
GERP RS		4.7
Varity_R		0.095
gMVP		0.33
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.0		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: rs140359227; hg19: chr5-169810853; COSMIC: COSV51136402;