3-54386694-G-GTTTTTTT

Variant names:

• chr3-54386694-G-GTTTTTTT
• rs62967361
• NM_018398.3:c.322-9_322-3dupTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS2

The NM_018398.3(CACNA2D3):​c.322-9_322-3dupTTTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,407,814 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: CACNA2D3 NM_018398.3 splice_acceptor, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.255
• Publications: 1 publications found

Genes affected

CACNA2D3 (HGNC:15460): (calcium voltage-gated channel auxiliary subunit alpha2delta 3) This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. Research on a highly similar protein in rabbit suggests the protein described in this record is cleaved into alpha-2 and delta subunits. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.01831502 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of 0 (no position change), new splice context is: ttttttttttttttttttAGcgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 3-54386694-G-GTTTTTTT is Benign according to our data. Variant chr3-54386694-G-GTTTTTTT is described in ClinVar as Likely_benign. ClinVar VariationId is 3357117.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018398.3. 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
	CACNA2D3	NM_018398.3	MANE Select	c.322-9_322-3dupTTTTTTT		splice_acceptor intron	N/A	NP_060868.2	Q8IZS8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.322-21_322-20insTTTTTTT		intron	N/A	ENSP00000419101.1	Q8IZS8-1
	CACNA2D3	ENST00000490478.5	TSL:1	c.40-21_40-20insTTTTTTT		intron	N/A	ENSP00000417279.1	Q8IZS8-2
	CACNA2D3	ENST00000468658.1	TSL:1	n.40-21_40-20insTTTTTTT		intron	N/A	ENSP00000417455.1	F8WAV4

Frequencies

GnomAD3 genomes AF: 0.000181 AC: 24 AN: 132530 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000759

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: 0.0000326

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000268 AC: 342 AN: 1275312 Hom.: 3 Cov.: 0 AF XY: 0.000275 AC XY: 173 AN XY: 628904

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

African (AFR) AF: 0.00121 AC: 33 AN: 27366

American (AMR) AF: 0.000669 AC: 18 AN: 26888

Ashkenazi Jewish (ASJ) AF: 0.000275 AC: 6 AN: 21842

East Asian (EAS) AF: 0.000516 AC: 18 AN: 34856

South Asian (SAS) AF: 0.000504 AC: 33 AN: 65470

European-Finnish (FIN) AF: 0.000201 AC: 7 AN: 34902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4818

European-Non Finnish (NFE) AF: 0.000208 AC: 209 AN: 1006112

Other (OTH) AF: 0.000339 AC: 18 AN: 53058

⚠️ 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: 0.000181 AC: 24 AN: 132502 Hom.: 0 Cov.: 21 AF XY: 0.000189 AC XY: 12 AN XY: 63464

African (AFR) AF: 0.000580 AC: 21 AN: 36236

American (AMR) AF: 0.0000758 AC: 1 AN: 13188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3198

East Asian (EAS) AF: 0.00 AC: 0 AN: 4552

South Asian (SAS) AF: 0.00 AC: 0 AN: 3984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 250

European-Non Finnish (NFE) AF: 0.0000327 AC: 2 AN: 61250

Other (OTH) AF: 0.00 AC: 0 AN: 1798

Alfa AF: 0.000386 Hom.: 22

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CACNA2D3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26

Splicing

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

Other links and lift over

dbSNP: rs62967361; hg19: chr3-54420721;