chr10-18340928-T-A

Variant names:

• chr10-18340928-T-A
• rs1401122407
• NM_201590.3:c.2T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_201590.3(CACNB2):​c.2T>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNB2 NM_201590.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.03
• 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, 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 84 codons. Genomic position: 18498433. Lost 0.137 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201590.3. 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_201590.3	MANE Plus Clinical	c.2T>A	p.Met1?	start_lost	Exon 1 of 13	NP_963884.2	Q08289-3
	CACNB2	NM_201596.3	MANE Select	c.214-60996T>A		intron	N/A	NP_963890.2	Q08289-1
	CACNB2	NM_201597.3		c.214-60996T>A		intron	N/A	NP_963891.1	Q08289-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.2T>A	p.Met1?	start_lost	Exon 1 of 13	ENSP00000366546.4	Q08289-3
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.214-60996T>A		intron	N/A	ENSP00000320025.8	Q08289-1
	CACNB2	ENST00000352115.10	TSL:1	c.214-60996T>A		intron	N/A	ENSP00000344474.6	Q08289-8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.97
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.34	D
PhyloP100		5.0
PROVEAN	Benign	1.1	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.81	P
Vest4		0.94
MutPred		0.79		Gain of MoRF binding (P = 0.0146)
MVP		0.91
ClinPred		0.68	D
GERP RS		5.2
PromoterAI		0.035	Neutral
Mutation Taster		=73/127	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1401122407; hg19: chr10-18629857;