7-82005506-GAAAAA-GAAAAAA

Variant names:

• chr7-82005506-G-GA
• rs576139922
• NM_000722.4:c.1516-10dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000722.4(CACNA2D1):​c.1516-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0616 in 1,135,952 control chromosomes in the GnomAD database, including 79 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.030 (77 hom., cov: 31)
  • Exomes 𝑓: 0.064 (2 hom.)
• Consequence: CACNA2D1 NM_000722.4 intron
• Clinical Significance: Benign no assertion criteria provided B:3
• Conservation: PhyloP100: 0.00
• 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 -9 ACMG points.

• BP6: Variant 7-82005506-G-GA is Benign according to our data. Variant chr7-82005506-G-GA is described in ClinVar as Benign. ClinVar VariationId is 1284308.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0901 is higher than 0.05.

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.1516-10dupT		intron	N/A	NP_000713.2
	CACNA2D1	NM_001366867.1		c.1516-10dupT		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.1516-10_1516-9insT		intron	N/A	ENSP00000349320.3
	CACNA2D1	ENST00000443883.2	TSL:5	c.1516-10_1516-9insT		intron	N/A	ENSP00000409374.2
	CACNA2D1	ENST00000705962.1		c.1432-10_1432-9insT		intron	N/A	ENSP00000516190.1

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 2720 AN: 91524 Hom.: 77 Cov.: 31

Gnomad AFR AF: 0.0931

Gnomad AMI AF: 0.0771

Gnomad AMR AF: 0.00967

Gnomad ASJ AF: 0.00196

Gnomad EAS AF: 0.00101

Gnomad SAS AF: 0.00181

Gnomad FIN AF: 0.00529

Gnomad MID AF: 0.0247

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0379 AC: 3820 AN: 100676 AF XY: 0.0355

Gnomad AFR exome AF: 0.0924

Gnomad AMR exome AF: 0.0569

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.0384

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0328

Gnomad OTH exome AF: 0.0403

GnomAD4 exome AF: 0.0644 AC: 67209 AN: 1044378 Hom.: 2 Cov.: 0 AF XY: 0.0607 AC XY: 31834 AN XY: 524122

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

African (AFR) AF: 0.109 AC: 2627 AN: 24070

American (AMR) AF: 0.0387 AC: 1149 AN: 29684

Ashkenazi Jewish (ASJ) AF: 0.0417 AC: 859 AN: 20588

East Asian (EAS) AF: 0.0350 AC: 1105 AN: 31582

South Asian (SAS) AF: 0.0380 AC: 2441 AN: 64206

European-Finnish (FIN) AF: 0.0251 AC: 1109 AN: 44250

Middle Eastern (MID) AF: 0.0451 AC: 174 AN: 3862

European-Non Finnish (NFE) AF: 0.0704 AC: 55065 AN: 781802

Other (OTH) AF: 0.0605 AC: 2680 AN: 44334

⚠️ 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: 0.0298 AC: 2728 AN: 91574 Hom.: 77 Cov.: 31 AF XY: 0.0297 AC XY: 1310 AN XY: 44174

African (AFR) AF: 0.0932 AC: 2434 AN: 26128

American (AMR) AF: 0.00966 AC: 87 AN: 9004

Ashkenazi Jewish (ASJ) AF: 0.00196 AC: 4 AN: 2036

East Asian (EAS) AF: 0.00101 AC: 3 AN: 2958

South Asian (SAS) AF: 0.00182 AC: 5 AN: 2754

European-Finnish (FIN) AF: 0.00529 AC: 31 AN: 5864

Middle Eastern (MID) AF: 0.0270 AC: 4 AN: 148

European-Non Finnish (NFE) AF: 0.00232 AC: 95 AN: 40956

Other (OTH) AF: 0.0213 AC: 26 AN: 1220

Alfa AF: 0.0133 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
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: rs576139922; hg19: chr7-81634822; COSMIC: COSV62373488; COSMIC: COSV62373488;