chr7-82060535-T-C

Variant names:

• chr7-82060535-T-C
• rs201901297
• NM_000722.4:c.780-8A>G

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.780-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,531,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005282
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.43
• 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
• 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

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics
• 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=-0.82).
• BP6: Variant 7-82060535-T-C is Benign according to our data. Variant chr7-82060535-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 532165.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.780-8A>G		splice_region intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.780-8A>G		splice_region intron	N/A	NP_001353796.1	P54289-1
	CACNA2D1	NM_001302890.2		c.780-8A>G		splice_region intron	N/A	NP_001289819.1	E7ERK3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.780-8A>G		splice_region intron	N/A	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000423588.1	TSL:1	c.780-8A>G		splice_region intron	N/A	ENSP00000405395.1	E7ERK3
	CACNA2D1	ENST00000443883.2	TSL:5	c.780-8A>G		splice_region intron	N/A	ENSP00000409374.2	H0Y715

Frequencies

GnomAD3 genomes AF: 0.000753 AC: 114 AN: 151364 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.000164 AC: 41 AN: 249416 AF XY: 0.000119

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 160 AN: 1379536 Hom.: 1 Cov.: 24 AF XY: 0.000114 AC XY: 79 AN XY: 690988

African (AFR) AF: 0.00248 AC: 79 AN: 31870

American (AMR) AF: 0.000112 AC: 5 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25442

East Asian (EAS) AF: 0.00 AC: 0 AN: 39146

South Asian (SAS) AF: 0.00 AC: 0 AN: 84534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51946

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5602

European-Non Finnish (NFE) AF: 0.0000539 AC: 56 AN: 1038928

Other (OTH) AF: 0.000330 AC: 19 AN: 57564

GnomAD4 genome AF: 0.000753 AC: 114 AN: 151480 Hom.: 0 Cov.: 29 AF XY: 0.000689 AC XY: 51 AN XY: 73968

African (AFR) AF: 0.00249 AC: 103 AN: 41360

American (AMR) AF: 0.000132 AC: 2 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5026

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10486

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67904

Other (OTH) AF: 0.000952 AC: 2 AN: 2100

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000903

ClinVar

ClinVar submissions

Significance: 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	-0.82
CADD	Benign	2.9
DANN	Benign	0.65
PhyloP100		-1.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.0040
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: rs201901297; hg19: chr7-81689851;