chr10-18140701-G-A

Variant names:

• chr10-18140701-G-A
• rs189082354
• NM_201596.3:c.-36G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201596.3(CACNB2):​c.-36G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,568,188 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (26 hom.)
• Consequence: CACNB2 NM_201596.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0330
• Publications: 0 publications found

Genes affected

CACNB2 (HGNC:1402): (calcium voltage-gated channel auxiliary subunit beta 2) This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. The gene product was originally identified as an antigen target in Lambert-Eaton myasthenic syndrome, an autoimmune disorder. Mutations in this gene are associated with Brugada syndrome. Alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Feb 2013]

CACNB2 Gene-Disease associations (from GenCC):

• Brugada syndrome 4

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• cardiogenetic disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 10-18140701-G-A is Benign according to our data. Variant chr10-18140701-G-A is described in ClinVar as Benign. ClinVar VariationId is 1292373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0115 (1754/152256) while in subpopulation AFR AF = 0.0393 (1634/41574). AF 95% confidence interval is 0.0377. There are 37 homozygotes in GnomAd4. There are 779 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1754 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201596.3. 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
	CACNB2	NM_201596.3	MANE Select	c.-36G>A		5_prime_UTR	Exon 1 of 14	NP_963890.2	Q08289-1
	CACNB2	NM_201597.3		c.-36G>A		5_prime_UTR	Exon 1 of 14	NP_963891.1	Q08289-8
	CACNB2	NM_201571.4		c.-479G>A		5_prime_UTR	Exon 1 of 14	NP_963865.2	Q08289-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.-36G>A		5_prime_UTR	Exon 1 of 14	ENSP00000320025.8	Q08289-1
	CACNB2	ENST00000352115.10	TSL:1	c.-36G>A		upstream_gene	N/A	ENSP00000344474.6	Q08289-8
	CACNB2	ENST00000377328.5	TSL:1	c.-36G>A		upstream_gene	N/A	ENSP00000366545.1	A6PVM6

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1752 AN: 152142 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00314 AC: 593 AN: 188872 AF XY: 0.00273

Gnomad AFR exome AF: 0.0415

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.000228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000276

Gnomad OTH exome AF: 0.00143

GnomAD4 exome AF: 0.00145 AC: 2049 AN: 1415932 Hom.: 26 Cov.: 28 AF XY: 0.00138 AC XY: 968 AN XY: 702180

African (AFR) AF: 0.0386 AC: 1267 AN: 32794

American (AMR) AF: 0.00274 AC: 109 AN: 39726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25430

East Asian (EAS) AF: 0.00 AC: 0 AN: 38294

South Asian (SAS) AF: 0.00260 AC: 212 AN: 81474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49168

Middle Eastern (MID) AF: 0.00495 AC: 23 AN: 4650

European-Non Finnish (NFE) AF: 0.000245 AC: 266 AN: 1085798

Other (OTH) AF: 0.00294 AC: 172 AN: 58598

GnomAD4 genome AF: 0.0115 AC: 1754 AN: 152256 Hom.: 37 Cov.: 32 AF XY: 0.0105 AC XY: 779 AN XY: 74434

African (AFR) AF: 0.0393 AC: 1634 AN: 41574

American (AMR) AF: 0.00359 AC: 55 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68002

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.00598 Hom.: 3

Bravo AF: 0.0125

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		-0.033
PromoterAI		0.11	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs189082354; hg19: chr10-18429630;