chr3-54879327-CTT-C

Variant names:

• chr3-54879327-CTT-C
• rs35536476
• NM_018398.3:c.1783-10_1783-9delTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_018398.3(CACNA2D3):​c.1783-10_1783-9delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,330,808 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 0)
  • Exomes 𝑓: 0.029 (1 hom.)
• Consequence: CACNA2D3 NM_018398.3 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.06
• 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]

CACNA2D3-AS1 (HGNC:40702): (CACNA2D3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 3-54879327-CTT-C is Benign according to our data. Variant chr3-54879327-CTT-C is described in ClinVar as Benign. ClinVar VariationId is 3037580.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1783-10_1783-9delTT		intron	N/A	NP_060868.2	Q8IZS8-1
	CACNA2D3-AS1	NR_046666.1		n.534-385_534-384delAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D3	ENST00000474759.6	TSL:1 MANE Select	c.1783-22_1783-21delTT		intron	N/A	ENSP00000419101.1	Q8IZS8-1
	CACNA2D3	ENST00000490478.5	TSL:1	c.1501-22_1501-21delTT		intron	N/A	ENSP00000417279.1	Q8IZS8-2
	CACNA2D3	ENST00000468658.1	TSL:1	n.*1197-22_*1197-21delTT		intron	N/A	ENSP00000417455.1	F8WAV4

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 406 AN: 143804 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00200

Gnomad SAS AF: 0.000884

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00333

Gnomad OTH AF: 0.00557

GnomAD2 exomes AF: 0.0696 AC: 11024 AN: 158340 AF XY: 0.0672

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.0608

Gnomad EAS exome AF: 0.175

Gnomad FIN exome AF: 0.0601

Gnomad NFE exome AF: 0.0446

Gnomad OTH exome AF: 0.0572

GnomAD4 exome AF: 0.0291 AC: 34515 AN: 1186966 Hom.: 1 AF XY: 0.0297 AC XY: 17653 AN XY: 593630

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

African (AFR) AF: 0.0184 AC: 492 AN: 26770

American (AMR) AF: 0.111 AC: 3307 AN: 29782

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 767 AN: 21822

East Asian (EAS) AF: 0.135 AC: 3603 AN: 26662

South Asian (SAS) AF: 0.0460 AC: 3173 AN: 68970

European-Finnish (FIN) AF: 0.0407 AC: 1662 AN: 40878

Middle Eastern (MID) AF: 0.0227 AC: 106 AN: 4662

European-Non Finnish (NFE) AF: 0.0218 AC: 20013 AN: 917884

Other (OTH) AF: 0.0281 AC: 1392 AN: 49536

⚠️ 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: 0.00283 AC: 407 AN: 143842 Hom.: 1 Cov.: 0 AF XY: 0.00271 AC XY: 189 AN XY: 69680

African (AFR) AF: 0.00118 AC: 46 AN: 39102

American (AMR) AF: 0.00659 AC: 96 AN: 14568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3374

East Asian (EAS) AF: 0.00220 AC: 11 AN: 4992

South Asian (SAS) AF: 0.000889 AC: 4 AN: 4500

European-Finnish (FIN) AF: 0.00236 AC: 20 AN: 8492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00334 AC: 219 AN: 65664

Other (OTH) AF: 0.00553 AC: 11 AN: 1988

Alfa AF: 0.0243 Hom.: 445

ClinVar

ClinVar submissions

Significance: 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		2.1
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: rs35536476; hg19: chr3-54913354;