7-81950516-TAAAAA-TAAAAAA

Variant names:

• chr7-81950516-T-TA
• rs367960608
• NM_000722.4:c.3160-9dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000722.4(CACNA2D1):​c.3160-9dupT variant causes a intron change. The variant allele was found at a frequency of 0.0847 in 1,423,610 control chromosomes in the GnomAD database, including 2,403 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (434 hom., cov: 31)
  • Exomes 𝑓: 0.086 (1969 hom.)
• Consequence: CACNA2D1 NM_000722.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.16
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 7-81950516-T-TA is Benign according to our data. Variant chr7-81950516-T-TA is described in ClinVar as Benign. ClinVar VariationId is 215476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0882 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	NM_000722.4	MANE Select	c.3160-9dupT		intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.3196-9dupT		intron	N/A	NP_001353796.1	P54289-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.3160-9_3160-8insT		intron	N/A	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000443883.2	TSL:5	c.3196-9_3196-8insT		intron	N/A	ENSP00000409374.2	H0Y715
	CACNA2D1	ENST00000957014.1		c.3181-9_3181-8insT		intron	N/A	ENSP00000627073.1

Frequencies

GnomAD3 genomes AF: 0.0745 AC: 10994 AN: 147474 Hom.: 433 Cov.: 31

Gnomad AFR AF: 0.0673

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0921

Gnomad ASJ AF: 0.0345

Gnomad EAS AF: 0.0184

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.0685

Gnomad MID AF: 0.0516

Gnomad NFE AF: 0.0828

Gnomad OTH AF: 0.0729

GnomAD2 exomes AF: 0.0970 AC: 15541 AN: 160184 AF XY: 0.0949

Gnomad AFR exome AF: 0.0793

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.0524

Gnomad EAS exome AF: 0.0255

Gnomad FIN exome AF: 0.0874

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0995

GnomAD4 exome AF: 0.0858 AC: 109545 AN: 1276046 Hom.: 1969 Cov.: 31 AF XY: 0.0851 AC XY: 54004 AN XY: 634724

African (AFR) AF: 0.0682 AC: 1946 AN: 28534

American (AMR) AF: 0.122 AC: 4479 AN: 36628

Ashkenazi Jewish (ASJ) AF: 0.0445 AC: 964 AN: 21680

East Asian (EAS) AF: 0.0216 AC: 719 AN: 33244

South Asian (SAS) AF: 0.0702 AC: 5046 AN: 71902

European-Finnish (FIN) AF: 0.0757 AC: 3488 AN: 46084

Middle Eastern (MID) AF: 0.0556 AC: 283 AN: 5086

European-Non Finnish (NFE) AF: 0.0901 AC: 88356 AN: 981168

Other (OTH) AF: 0.0824 AC: 4264 AN: 51720

GnomAD4 genome AF: 0.0746 AC: 11009 AN: 147564 Hom.: 434 Cov.: 31 AF XY: 0.0733 AC XY: 5262 AN XY: 71820

African (AFR) AF: 0.0674 AC: 2710 AN: 40234

American (AMR) AF: 0.0923 AC: 1357 AN: 14702

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 117 AN: 3392

East Asian (EAS) AF: 0.0184 AC: 93 AN: 5050

South Asian (SAS) AF: 0.0605 AC: 282 AN: 4660

European-Finnish (FIN) AF: 0.0685 AC: 660 AN: 9634

Middle Eastern (MID) AF: 0.0486 AC: 14 AN: 288

European-Non Finnish (NFE) AF: 0.0828 AC: 5523 AN: 66692

Other (OTH) AF: 0.0727 AC: 146 AN: 2008

Alfa AF: 0.0378 Hom.: 18

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Brugada syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs367960608; hg19: chr7-81579832;