ENST00000377315.6:c.-323G>T

Variant names:

• chr10-18400709-G-T
• rs61839258
• ENST00000377315.6:c.-323G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000377315.6(CACNB2):​c.-323G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,092,234 control chromosomes in the GnomAD database, including 14,681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1749 hom., cov: 31)
  • Exomes 𝑓: 0.16 (12932 hom.)
• Consequence: CACNB2 ENST00000377315.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0370
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-18400709-G-T is Benign according to our data. Variant chr10-18400709-G-T is described in ClinVar as Benign. ClinVar VariationId is 1232266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.214-1215G>T		intron_variant	Intron 2 of 13	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.52-1215G>T		intron_variant	Intron 1 of 12	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.214-1215G>T		intron_variant	Intron 2 of 13	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.52-1215G>T		intron_variant	Intron 1 of 12	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21354 AN: 150892 Hom.: 1754 Cov.: 31

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.160 AC: 150759 AN: 941226 Hom.: 12932 Cov.: 32 AF XY: 0.159 AC XY: 70075 AN XY: 440156

African (AFR) AF: 0.0483 AC: 967 AN: 20024

American (AMR) AF: 0.108 AC: 597 AN: 5512

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 1086 AN: 9276

East Asian (EAS) AF: 0.179 AC: 2074 AN: 11556

South Asian (SAS) AF: 0.168 AC: 3508 AN: 20884

European-Finnish (FIN) AF: 0.136 AC: 836 AN: 6134

Middle Eastern (MID) AF: 0.167 AC: 355 AN: 2128

European-Non Finnish (NFE) AF: 0.164 AC: 136074 AN: 831274

Other (OTH) AF: 0.153 AC: 5262 AN: 34438

GnomAD4 genome AF: 0.141 AC: 21345 AN: 151008 Hom.: 1749 Cov.: 31 AF XY: 0.145 AC XY: 10708 AN XY: 73698

African (AFR) AF: 0.0588 AC: 2414 AN: 41026

American (AMR) AF: 0.140 AC: 2120 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 501 AN: 3466

East Asian (EAS) AF: 0.230 AC: 1176 AN: 5122

South Asian (SAS) AF: 0.192 AC: 919 AN: 4778

European-Finnish (FIN) AF: 0.238 AC: 2443 AN: 10276

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.168 AC: 11370 AN: 67870

Other (OTH) AF: 0.123 AC: 258 AN: 2092

Alfa AF: 0.149 Hom.: 612

Bravo AF: 0.127

Asia WGS AF: 0.193 AC: 670 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.59
PhyloP100		-0.037
PromoterAI		-0.077	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs61839258; hg19: chr10-18689638;