rs148414498

Variant names:

• chr10-18536187-G-A
• rs148414498
• NM_201596.3:c.1293G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-18536187-G-A
• chr10-18536187-G-C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_201596.3(CACNB2):​c.1293G>A​(p.Gln431Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,532,870 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00088 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CACNB2 NM_201596.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.35
• Publications: 2 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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• 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

CACNB2-AS1 (HGNC:58168):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 10-18536187-G-A is Benign according to our data. Variant chr10-18536187-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.35 with no splicing effect.
• BS2: High AC in GnomAd4 at 128 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.1293G>A	p.Gln431Gln	synonymous	Exon 12 of 14	NP_963890.2	Q08289-1
	CACNB2	NM_201590.3	MANE Plus Clinical	c.1131G>A	p.Gln377Gln	synonymous	Exon 11 of 13	NP_963884.2	Q08289-3
	CACNB2	NM_201597.3		c.1221G>A	p.Gln407Gln	synonymous	Exon 12 of 14	NP_963891.1	Q08289-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.1293G>A	p.Gln431Gln	synonymous	Exon 12 of 14	ENSP00000320025.8	Q08289-1
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.1131G>A	p.Gln377Gln	synonymous	Exon 11 of 13	ENSP00000366546.4	Q08289-3
	CACNB2	ENST00000352115.10	TSL:1	c.1221G>A	p.Gln407Gln	synonymous	Exon 12 of 14	ENSP00000344474.6	Q08289-8

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 129 AN: 145416 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00180

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000330 AC: 83 AN: 251386 AF XY: 0.000272

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000154 AC: 213 AN: 1387366 Hom.: 0 Cov.: 26 AF XY: 0.000160 AC XY: 111 AN XY: 692058

African (AFR) AF: 0.00430 AC: 133 AN: 30944

American (AMR) AF: 0.0000926 AC: 4 AN: 43190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24544

East Asian (EAS) AF: 0.00 AC: 0 AN: 35288

South Asian (SAS) AF: 0.000682 AC: 58 AN: 85094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5494

European-Non Finnish (NFE) AF: 0.00000568 AC: 6 AN: 1056028

Other (OTH) AF: 0.000213 AC: 12 AN: 56292

GnomAD4 genome AF: 0.000880 AC: 128 AN: 145504 Hom.: 2 Cov.: 30 AF XY: 0.000879 AC XY: 62 AN XY: 70548

African (AFR) AF: 0.00306 AC: 119 AN: 38912

American (AMR) AF: 0.0000695 AC: 1 AN: 14388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 4728

South Asian (SAS) AF: 0.00180 AC: 8 AN: 4442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67094

Other (OTH) AF: 0.00 AC: 0 AN: 2032

Alfa AF: 0.000343 Hom.: 0

Bravo AF: 0.000914

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Brugada syndrome 4 (1)
-	-	1	CACNB2-related disorder (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.7
DANN	Benign	0.86
PhyloP100		2.3
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs148414498; hg19: chr10-18825116; COSMIC: COSV99994427; COSMIC: COSV99994427;