chr7-82136680-C-CAAAA

Variant names:

• chr7-82136680-C-CAAAA
• rs142849270
• NM_000722.4:c.355-8_355-5dupTTTT

Variant summary

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

The NM_000722.4(CACNA2D1):​c.355-8_355-5dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000336 in 1,190,286 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: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CACNA2D1 NM_000722.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0210
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D1	NM_000722.4	c.355-8_355-5dupTTTT		splice_region_variant, intron_variant	Intron 4 of 38	ENST00000356860.8	NP_000713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8	c.355-5_355-4insTTTT		splice_region_variant, intron_variant	Intron 4 of 38	1	NM_000722.4	ENSP00000349320.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000336 AC: 4 AN: 1190286 Hom.: 0 Cov.: 25 AF XY: 0.00000509 AC XY: 3 AN XY: 589936

⚠️ 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: 27290

American (AMR) AF: 0.00 AC: 0 AN: 32526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20552

East Asian (EAS) AF: 0.00 AC: 0 AN: 31730

South Asian (SAS) AF: 0.0000152 AC: 1 AN: 65800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4832

European-Non Finnish (NFE) AF: 0.00000217 AC: 2 AN: 920766

Other (OTH) AF: 0.00 AC: 0 AN: 48816

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;