chr7-81974555-G-GA

Variant names:

• chr7-81974555-G-GA
• rs3083235
• NM_000722.4:c.1956-4dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000722.4(CACNA2D1):​c.1956-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,332,840 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0030 (1 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.195
• Publications: 3 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 -8 ACMG points.

• BP6: Variant 7-81974555-G-GA is Benign according to our data. Variant chr7-81974555-G-GA is described in ClinVar as Benign. ClinVar VariationId is 518634.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.1956-4dupT		splice_region intron	N/A	NP_000713.2
	CACNA2D1	NM_001366867.1		c.1992-4dupT		splice_region intron	N/A	NP_001353796.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.1956-4_1956-3insT		splice_region intron	N/A	ENSP00000349320.3
	CACNA2D1	ENST00000443883.2	TSL:5	c.1992-4_1992-3insT		splice_region intron	N/A	ENSP00000409374.2
	CACNA2D1	ENST00000705962.1		c.1836-4_1836-3insT		splice_region intron	N/A	ENSP00000516190.1

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 201 AN: 147512 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000475

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00138

Gnomad SAS AF: 0.000642

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000419

Gnomad OTH AF: 0.000492

GnomAD2 exomes AF: 0.00212 AC: 411 AN: 194206 AF XY: 0.00213

Gnomad AFR exome AF: 0.00470

Gnomad AMR exome AF: 0.00274

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00324

Gnomad FIN exome AF: 0.000958

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00301 AC: 3571 AN: 1185246 Hom.: 1 Cov.: 18 AF XY: 0.00285 AC XY: 1706 AN XY: 599354

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00589 AC: 161 AN: 27322

American (AMR) AF: 0.00206 AC: 85 AN: 41238

Ashkenazi Jewish (ASJ) AF: 0.00301 AC: 70 AN: 23292

East Asian (EAS) AF: 0.00263 AC: 95 AN: 36166

South Asian (SAS) AF: 0.00187 AC: 142 AN: 75874

European-Finnish (FIN) AF: 0.00164 AC: 81 AN: 49480

Middle Eastern (MID) AF: 0.00166 AC: 8 AN: 4810

European-Non Finnish (NFE) AF: 0.00319 AC: 2797 AN: 877008

Other (OTH) AF: 0.00264 AC: 132 AN: 50056

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00135 AC: 199 AN: 147594 Hom.: 1 Cov.: 30 AF XY: 0.00137 AC XY: 98 AN XY: 71756

African (AFR) AF: 0.00378 AC: 152 AN: 40184

American (AMR) AF: 0.000474 AC: 7 AN: 14764

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3458

East Asian (EAS) AF: 0.00139 AC: 7 AN: 5050

South Asian (SAS) AF: 0.000644 AC: 3 AN: 4662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000419 AC: 28 AN: 66890

Other (OTH) AF: 0.000487 AC: 1 AN: 2054

Alfa AF: 0.00405 Hom.: 35

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism

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: rs3083235; hg19: chr7-81603871;