GeneBe

rs33972365

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_172364.5(CACNA2D4):​c.2517G>T​(p.Ala839Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A839A) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA2D4
NM_172364.5 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.06

Publications

6 publications found
Variant links:
Genes affected
CACNA2D4 (HGNC:20202): (calcium voltage-gated channel auxiliary subunit alpha2delta 4) 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]
CACNA2D4 Gene-Disease associations (from GenCC):
  • inherited retinal dystrophy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • retinal cone dystrophy 4
    Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
  • cone-rod dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP7
Synonymous conserved (PhyloP=-2.06 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA2D4NM_172364.5 linkc.2517G>T p.Ala839Ala synonymous_variant Exon 26 of 38 ENST00000382722.10 NP_758952.4 Q7Z3S7-1
CACNA2D4XM_011521041.3 linkc.2454G>T p.Ala818Ala synonymous_variant Exon 25 of 36 XP_011519343.1
CACNA2D4XM_047429897.1 linkc.2445G>T p.Ala815Ala synonymous_variant Exon 25 of 36 XP_047285853.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA2D4ENST00000382722.10 linkc.2517G>T p.Ala839Ala synonymous_variant Exon 26 of 38 1 NM_172364.5 ENSP00000372169.4 Q7Z3S7-1
CACNA2D4ENST00000586184.5 linkc.2517G>T p.Ala839Ala synonymous_variant Exon 26 of 37 5 ENSP00000465060.1 Q7Z3S7-5
CACNA2D4ENST00000587995.5 linkc.2442G>T p.Ala814Ala synonymous_variant Exon 25 of 37 5 ENSP00000465372.1 K7EJY1
CACNA2D4ENST00000585708.5 linkc.2325G>T p.Ala775Ala synonymous_variant Exon 26 of 37 5 ENSP00000467697.1 Q7Z3S7-6
CACNA2D4ENST00000588077.5 linkc.2325G>T p.Ala775Ala synonymous_variant Exon 26 of 38 5 ENSP00000468530.1 Q7Z3S7-4
CACNA2D4ENST00000444595.6 linkn.*763G>T non_coding_transcript_exon_variant Exon 26 of 37 1 ENSP00000403371.2 E7EUE0
CACNA2D4ENST00000537784.5 linkn.357G>T non_coding_transcript_exon_variant Exon 4 of 15 1 ENSP00000440231.2 X6RLU5
CACNA2D4ENST00000444595.6 linkn.*763G>T 3_prime_UTR_variant Exon 26 of 37 1 ENSP00000403371.2 E7EUE0

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD2 exomes
AF:
0.00000803
AC:
2
AN:
249110
AF XY:
0.00000740
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461560
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727066
show subpopulations
⚠️ 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:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26120
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53292
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111848
Other (OTH)
AF:
0.00
AC:
0
AN:
60372
⚠️ 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.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
CADD
Benign
0.076
DANN
Benign
0.85
PhyloP100
-2.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs33972365; hg19: chr12-1949939; API