Genetic Variant CACNA2D4:p.Ala839Ala (chr12-1840773-C-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_172364.5(CACNA2D4):c.2517G>C(p.Ala839Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 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: 6.8e-7 ( 0 hom. )

Consequence

CACNA2D4
NM_172364.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.06

Publications

0 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

CACNA2D4 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP7

Synonymous conserved (PhyloP=-2.06 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.2517G>C	p.Ala839Ala	synonymous_variant	Exon 26 of 38	ENST00000382722.10	NP_758952.4	Q7Z3S7-1
CACNA2D4	XM_011521041.3 link	c.2454G>C	p.Ala818Ala	synonymous_variant	Exon 25 of 36		XP_011519343.1
CACNA2D4	XM_047429897.1 link	c.2445G>C	p.Ala815Ala	synonymous_variant	Exon 25 of 36		XP_047285853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 link	c.2517G>C	p.Ala839Ala	synonymous_variant	Exon 26 of 38	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 link	c.2517G>C	p.Ala839Ala	synonymous_variant	Exon 26 of 37	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 link	c.2442G>C	p.Ala814Ala	synonymous_variant	Exon 25 of 37	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 link	c.2325G>C	p.Ala775Ala	synonymous_variant	Exon 26 of 37	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 link	c.2325G>C	p.Ala775Ala	synonymous_variant	Exon 26 of 38	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000444595.6 link	n.*763G>C		non_coding_transcript_exon_variant	Exon 26 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.357G>C		non_coding_transcript_exon_variant	Exon 4 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000444595.6 link	n.*763G>C		3_prime_UTR_variant	Exon 26 of 37	1		ENSP00000403371.2	E7EUE0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461560

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111848

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.089

(source)

DANN

Benign

0.78

PhyloP100

-2.1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over