10-18340958-C-T

Variant names:

• chr10-18340958-C-T
• rs587777742
• NM_201590.3:c.32C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_201590.3(CACNB2):​c.32C>T​(p.Thr11Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNB2 NM_201590.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.43
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Laboratory for Molecular Medicine
• Brugada syndrome 1

  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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 10-18340958-C-T is Pathogenic according to our data. Variant chr10-18340958-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 156228.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	NM_201590.3	MANE Plus Clinical	c.32C>T	p.Thr11Ile	missense	Exon 1 of 13	NP_963884.2
	CACNB2	NM_201596.3	MANE Select	c.214-60966C>T		intron	N/A	NP_963890.2
	CACNB2	NM_201597.3		c.214-60966C>T		intron	N/A	NP_963891.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.32C>T	p.Thr11Ile	missense	Exon 1 of 13	ENSP00000366546.4
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.214-60966C>T		intron	N/A	ENSP00000320025.8
	CACNB2	ENST00000352115.10	TSL:1	c.214-60966C>T		intron	N/A	ENSP00000344474.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33476

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: 86252

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: 1111992

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Brugada syndrome 4 Pathogenic:1

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	14
DANN	Uncertain	1.0
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.30	T
PhyloP100		3.4
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.46
Sift	Benign	0.35	T
Sift4G	Benign	0.070	T
Polyphen		0.13	B
Vest4		0.47
MutPred		0.85		Gain of helix (P = 0.0117)
MVP		0.93
ClinPred		0.45	T
GERP RS		5.2
PromoterAI		-0.028	Neutral
Mutation Taster		=94/6	disease causing (ClinVar)

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: rs587777742; hg19: chr10-18629887;