7-82136680-CAA-CAAAAA

Variant names:

• chr7-82136680-C-CAAA
• rs142849270
• NM_000722.4:c.355-7_355-5dupTTT

Variant summary

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

The NM_000722.4(CACNA2D1):​c.355-7_355-5dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,329,318 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 0.0000072 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0210
• 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
• 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.355-7_355-5dupTTT		splice_region intron	N/A	NP_000713.2
	CACNA2D1	NM_001366867.1		c.355-7_355-5dupTTT		splice_region intron	N/A	NP_001353796.1
	CACNA2D1	NM_001302890.2		c.355-7_355-5dupTTT		splice_region intron	N/A	NP_001289819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.355-5_355-4insTTT		splice_region intron	N/A	ENSP00000349320.3
	CACNA2D1	ENST00000423588.1	TSL:1	c.355-5_355-4insTTT		splice_region intron	N/A	ENSP00000405395.1
	CACNA2D1	ENST00000443883.2	TSL:5	c.355-5_355-4insTTT		splice_region intron	N/A	ENSP00000409374.2

Frequencies

GnomAD3 genomes AF: 0.00000718 AC: 1 AN: 139246 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000687 AC: 8 AN: 116500 AF XY: 0.0000801

Gnomad AFR exome AF: 0.000122

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000383

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000429 AC: 51 AN: 1189980 Hom.: 0 Cov.: 25 AF XY: 0.0000627 AC XY: 37 AN XY: 589768

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

African (AFR) AF: 0.0000366 AC: 1 AN: 27286

American (AMR) AF: 0.0000615 AC: 2 AN: 32518

Ashkenazi Jewish (ASJ) AF: 0.0000487 AC: 1 AN: 20548

East Asian (EAS) AF: 0.0000630 AC: 2 AN: 31728

South Asian (SAS) AF: 0.000426 AC: 28 AN: 65734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37968

Middle Eastern (MID) AF: 0.000207 AC: 1 AN: 4832

European-Non Finnish (NFE) AF: 0.0000130 AC: 12 AN: 920570

Other (OTH) AF: 0.0000820 AC: 4 AN: 48796

⚠️ 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: 0.00000718 AC: 1 AN: 139338 Hom.: 0 Cov.: 30 AF XY: 0.0000149 AC XY: 1 AN XY: 67334

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

African (AFR) AF: 0.00 AC: 0 AN: 38266

American (AMR) AF: 0.00 AC: 0 AN: 13788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3286

East Asian (EAS) AF: 0.00 AC: 0 AN: 4836

South Asian (SAS) AF: 0.000228 AC: 1 AN: 4388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63460

Other (OTH) AF: 0.00 AC: 0 AN: 1914

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000318 Hom.: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.021

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142849270; hg19: chr7-81765996;