7-81950516-TAAAAA-TAAA

Variant names:

• chr7-81950516-TAA-T
• rs367960608
• NM_000722.4:c.3160-10_3160-9delTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000722.4(CACNA2D1):​c.3160-10_3160-9delTT variant causes a intron change. The variant allele was found at a frequency of 0.00000306 in 1,306,562 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CACNA2D1 NM_000722.4 intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3160-10_3160-9delTT		intron	N/A	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.3196-10_3196-9delTT		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.3160-10_3160-9delTT		intron	N/A	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000443883.2	TSL:5	c.3196-10_3196-9delTT		intron	N/A	ENSP00000409374.2	H0Y715
	CACNA2D1	ENST00000957014.1		c.3181-10_3181-9delTT		intron	N/A	ENSP00000627073.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000312 AC: 5 AN: 160184 AF XY: 0.0000232

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000997

Gnomad ASJ exome AF: 0.000163

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000306 AC: 4 AN: 1306562 Hom.: 0 AF XY: 0.00000462 AC XY: 3 AN XY: 649792

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

African (AFR) AF: 0.00 AC: 0 AN: 29360

American (AMR) AF: 0.0000533 AC: 2 AN: 37552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22376

East Asian (EAS) AF: 0.00 AC: 0 AN: 34358

South Asian (SAS) AF: 0.0000270 AC: 2 AN: 74030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5198

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1003364

Other (OTH) AF: 0.00 AC: 0 AN: 53144

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
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: rs367960608; hg19: chr7-81579832;