7-82005506-GAAAAA-GAA

Variant names:

• chr7-82005506-GAAA-G
• rs576139922
• NM_000722.4:c.1516-12_1516-10delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000722.4(CACNA2D1):​c.1516-12_1516-10delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,199,744 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: CACNA2D1 NM_000722.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.1516-12_1516-10delTTT		intron	N/A	NP_000713.2
	CACNA2D1	NM_001366867.1		c.1516-12_1516-10delTTT		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.1516-12_1516-10delTTT		intron	N/A	ENSP00000349320.3
	CACNA2D1	ENST00000443883.2	TSL:5	c.1516-12_1516-10delTTT		intron	N/A	ENSP00000409374.2
	CACNA2D1	ENST00000705962.1		c.1432-12_1432-10delTTT		intron	N/A	ENSP00000516190.1

Frequencies

GnomAD3 genomes AF: 0.0000109 AC: 1 AN: 91630 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000308 AC: 31 AN: 100676 AF XY: 0.000298

Gnomad AFR exome AF: 0.000319

Gnomad AMR exome AF: 0.000142

Gnomad ASJ exome AF: 0.000197

Gnomad EAS exome AF: 0.000573

Gnomad FIN exome AF: 0.000256

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.000391

GnomAD4 exome AF: 0.000245 AC: 271 AN: 1108114 Hom.: 0 AF XY: 0.000246 AC XY: 137 AN XY: 557006

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

African (AFR) AF: 0.000432 AC: 11 AN: 25438

American (AMR) AF: 0.000316 AC: 10 AN: 31644

Ashkenazi Jewish (ASJ) AF: 0.0000910 AC: 2 AN: 21988

East Asian (EAS) AF: 0.0000875 AC: 3 AN: 34272

South Asian (SAS) AF: 0.000159 AC: 11 AN: 69284

European-Finnish (FIN) AF: 0.0000636 AC: 3 AN: 47154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4082

European-Non Finnish (NFE) AF: 0.000270 AC: 223 AN: 826936

Other (OTH) AF: 0.000169 AC: 8 AN: 47316

⚠️ 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: 0.0000109 AC: 1 AN: 91630 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 44176

African (AFR) AF: 0.0000384 AC: 1 AN: 26072

American (AMR) AF: 0.00 AC: 0 AN: 9010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2038

East Asian (EAS) AF: 0.00 AC: 0 AN: 2972

South Asian (SAS) AF: 0.00 AC: 0 AN: 2758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 162

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 41014

Other (OTH) AF: 0.00 AC: 0 AN: 1214

Alfa AF: 0.000328 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
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;