rs73298199

Variant names:

• chr12-48824661-C-A
• rs73298199
• NM_000725.4:c.408-8C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000725.4(CACNB3):​c.408-8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,612,758 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0095 (31 hom., cov: 30)
  • Exomes 𝑓: 0.00092 (21 hom.)
• Consequence: CACNB3 NM_000725.4 splice_region, intron
• Scores: Splicing: ADA: 0.002250
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.930
• Publications: 1 publications found

Genes affected

CACNB3 (HGNC:1403): (calcium voltage-gated channel auxiliary subunit beta 3) This gene encodes a regulatory beta subunit of the voltage-dependent calcium channel. Beta subunits are composed of five domains, which contribute to the regulation of surface expression and gating of calcium channels and may also play a role in the regulation of transcription factors and calcium transport. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-48824661-C-A is Benign according to our data. Variant chr12-48824661-C-A is described in ClinVar as Benign. ClinVar VariationId is 788882.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00953 (1450/152112) while in subpopulation AFR AF = 0.0333 (1381/41490). AF 95% confidence interval is 0.0318. There are 31 homozygotes in GnomAd4. There are 660 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000725.4. 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
	CACNB3	NM_000725.4	MANE Select	c.408-8C>A		splice_region intron	N/A	NP_000716.2
	CACNB3	NM_001206916.2		c.405-8C>A		splice_region intron	N/A	NP_001193845.1	P54284-4
	CACNB3	NM_001206917.2		c.369-8C>A		splice_region intron	N/A	NP_001193846.1	P54284-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB3	ENST00000301050.7	TSL:1 MANE Select	c.408-8C>A		splice_region intron	N/A	ENSP00000301050.2	P54284-1
	CACNB3	ENST00000536187.6	TSL:2	c.405-8C>A		splice_region intron	N/A	ENSP00000444160.2	P54284-4
	CACNB3	ENST00000861431.1		c.408-11C>A		intron	N/A	ENSP00000531490.1

Frequencies

GnomAD3 genomes AF: 0.00951 AC: 1445 AN: 151994 Hom.: 31 Cov.: 30

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00256 AC: 641 AN: 250814 AF XY: 0.00168

Gnomad AFR exome AF: 0.0365

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000919 AC: 1343 AN: 1460646 Hom.: 21 Cov.: 32 AF XY: 0.000802 AC XY: 583 AN XY: 726644

African (AFR) AF: 0.0342 AC: 1143 AN: 33436

American (AMR) AF: 0.00145 AC: 65 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1110970

Other (OTH) AF: 0.00164 AC: 99 AN: 60360

GnomAD4 genome AF: 0.00953 AC: 1450 AN: 152112 Hom.: 31 Cov.: 30 AF XY: 0.00888 AC XY: 660 AN XY: 74362

African (AFR) AF: 0.0333 AC: 1381 AN: 41490

American (AMR) AF: 0.00340 AC: 52 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67992

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00338 Hom.: 4

Bravo AF: 0.0103

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.4
DANN	Benign	0.56
PhyloP100		0.93
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.090
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: rs73298199; hg19: chr12-49218444;