5-170383792-C-T

Position:

• chr5-170383792-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_004137.4(KCNMB1):​c.193G>A​(p.Glu65Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0963 in 1,613,934 control chromosomes in the GnomAD database, including 8,040 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.088 (675 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7365 hom.)
• Consequence: KCNMB1 NM_004137.4 missense
• Clinical Significance: Benign; protective no assertion criteria provided B:2
• Conservation: PhyloP100: 1.17

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]

KCNIP1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013051927).
• BP6: Variant 5-170383792-C-T is Benign according to our data. Variant chr5-170383792-C-T is described in ClinVar as [Benign, protective]. Clinvar id is 5941.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMB1	NM_004137.4	c.193G>A	p.Glu65Lys	missense_variant	3/4	ENST00000274629.9	NP_004128.1
KCNIP1	NM_001034838.3	c.88+29828C>T		intron_variant			NP_001030010.1
KCNIP1	XM_017009407.2	c.88+29828C>T		intron_variant			XP_016864896.1
KCNIP1	XM_017009408.2	c.88+29828C>T		intron_variant			XP_016864897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMB1	ENST00000274629.9	c.193G>A	p.Glu65Lys	missense_variant	3/4	1	NM_004137.4	ENSP00000274629.3

Frequencies

GnomAD3 genomes AF: 0.0883 AC: 13431 AN: 152082 Hom.: 676 Cov.: 32

Gnomad AFR AF: 0.0560

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0723

Gnomad FIN AF: 0.0686

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0952

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.0994 AC: 24974 AN: 251146 Hom.: 1404 AF XY: 0.0984 AC XY: 13361 AN XY: 135748

Gnomad AFR exome AF: 0.0566

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.0955

Gnomad SAS exome AF: 0.0741

Gnomad FIN exome AF: 0.0691

Gnomad NFE exome AF: 0.0961

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0971 AC: 141940 AN: 1461734 Hom.: 7365 Cov.: 32 AF XY: 0.0965 AC XY: 70195 AN XY: 727164

Gnomad4 AFR exome AF: 0.0540

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.0772

Gnomad4 FIN exome AF: 0.0687

Gnomad4 NFE exome AF: 0.0969

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.0882 AC: 13431 AN: 152200 Hom.: 675 Cov.: 32 AF XY: 0.0883 AC XY: 6572 AN XY: 74404

Gnomad4 AFR AF: 0.0558

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.0725

Gnomad4 FIN AF: 0.0686

Gnomad4 NFE AF: 0.0952

Gnomad4 OTH AF: 0.100

Alfa AF: 0.0989 Hom.: 2016

Bravo AF: 0.0940

TwinsUK AF: 0.0933 AC: 346

ALSPAC AF: 0.106 AC: 408

ESP6500AA AF: 0.0604 AC: 266

ESP6500EA AF: 0.101 AC: 870

ExAC AF: 0.0954 AC: 11588

Asia WGS AF: 0.0850 AC: 296 AN: 3478

EpiCase AF: 0.0948

EpiControl AF: 0.0957

ClinVar

Significance: Benign; protective

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

KCNMB1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 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). -

Hypertension, diastolic, resistance to Benign:1

protective, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.68	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.053
Sift	Benign	0.17	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.051	B;B
Vest4		0.22
MPC		0.13
ClinPred		0.0040	T
GERP RS		3.6
Varity_R		0.12
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs11739136; hg19: chr5-169810796;