NM_000722.4:c.2309-9T>A

Variant names:

• chr7-81968982-A-T
• rs370816599
• NM_000722.4:c.2309-9T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000722.4(CACNA2D1):​c.2309-9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,444,342 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: CACNA2D1 NM_000722.4 intron
• Scores: Splicing: ADA: 0.00006580
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.941
• Publications: 0 publications found

Genes affected

CACNA2D1 (HGNC:1399): (calcium voltage-gated channel auxiliary subunit alpha2delta 1) The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]

CACNA2D1 Gene-Disease associations (from GenCC):

• short QT syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
• Brugada syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• developmental and epileptic encephalopathy 110

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-81968982-A-T is Benign according to our data. Variant chr7-81968982-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 463223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000722.4. 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
	CACNA2D1	NM_000722.4	MANE Select	c.2309-9T>A		intron	N/A	NP_000713.2
	CACNA2D1	NM_001366867.1		c.2345-9T>A		intron	N/A	NP_001353796.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.2309-9T>A		intron	N/A	ENSP00000349320.3
	CACNA2D1	ENST00000443883.2	TSL:5	c.2345-9T>A		intron	N/A	ENSP00000409374.2
	CACNA2D1	ENST00000957014.1		c.2330-9T>A		intron	N/A	ENSP00000627073.1

Frequencies

GnomAD3 genomes AF: 0.000681 AC: 103 AN: 151322 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000267

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.000353 AC: 86 AN: 243324 AF XY: 0.000370

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.0000485

Gnomad NFE exome AF: 0.000146

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.000171 AC: 221 AN: 1292902 Hom.: 1 Cov.: 20 AF XY: 0.000170 AC XY: 111 AN XY: 652304

African (AFR) AF: 0.00163 AC: 49 AN: 29988

American (AMR) AF: 0.00109 AC: 48 AN: 44024

Ashkenazi Jewish (ASJ) AF: 0.0000403 AC: 1 AN: 24804

East Asian (EAS) AF: 0.000155 AC: 6 AN: 38660

South Asian (SAS) AF: 0.000233 AC: 19 AN: 81408

European-Finnish (FIN) AF: 0.0000387 AC: 2 AN: 51622

Middle Eastern (MID) AF: 0.000188 AC: 1 AN: 5326

European-Non Finnish (NFE) AF: 0.0000852 AC: 82 AN: 962568

Other (OTH) AF: 0.000239 AC: 13 AN: 54502

GnomAD4 genome AF: 0.000680 AC: 103 AN: 151440 Hom.: 0 Cov.: 32 AF XY: 0.000743 AC XY: 55 AN XY: 74010

African (AFR) AF: 0.00152 AC: 63 AN: 41468

American (AMR) AF: 0.00106 AC: 16 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000267 AC: 18 AN: 67496

Other (OTH) AF: 0.000477 AC: 1 AN: 2096

Alfa AF: 0.000528 Hom.: 0

Bravo AF: 0.000623

Asia WGS AF: 0.00145 AC: 5 AN: 3460

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Brugada syndrome (1)
-	-	1	CACNA2D1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.13
DANN	Benign	0.33
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.056
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: rs370816599; hg19: chr7-81598298;