5-170385394-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_004137.4(KCNMB1):c.54C>T(p.Cys18=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00959 in 1,614,034 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (67 hom.)
• Consequence: KCNMB1 NM_004137.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.720

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 5-170385394-G-A is Benign according to our data. Variant chr5-170385394-G-A is described in ClinVar as [Benign]. Clinvar id is 779246.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.72 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMB1	NM_004137.4	c.54C>T	p.Cys18=	synonymous_variant	2/4	ENST00000274629.9
KCNIP1	NM_001034838.3	c.88+31430G>A		intron_variant
KCNIP1	XM_017009407.2	c.88+31430G>A		intron_variant
KCNIP1	XM_017009408.2	c.88+31430G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMB1	ENST00000274629.9	c.54C>T	p.Cys18=	synonymous_variant	2/4	1	NM_004137.4	P1

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 1012 AN: 152052 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00651 AC: 1638 AN: 251424 Hom.: 9 AF XY: 0.00654 AC XY: 889 AN XY: 135878

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00714

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00443

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00990 AC: 14466 AN: 1461866 Hom.: 67 Cov.: 32 AF XY: 0.00963 AC XY: 7000 AN XY: 727236

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.00722

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.00382

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00894

GnomAD4 genome AF: 0.00665 AC: 1012 AN: 152168 Hom.: 4 Cov.: 32 AF XY: 0.00641 AC XY: 477 AN XY: 74398

Gnomad4 AFR AF: 0.00229

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00841 Hom.: 2

Bravo AF: 0.00672

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0114

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	9.1
Dann	Benign	0.80

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: rs45574034; hg19: chr5-169812398; COSMIC: COSV51137526; COSMIC: COSV51137526;