Genetic Variant CACNA2D4:p.Leu679Met (chr12-1856203-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_172364.5(CACNA2D4):c.2035C>A(p.Leu679Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L679L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CACNA2D4
NM_172364.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.137

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: 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
CACNA2D4	NM_172364.5 link	c.2035C>A	p.Leu679Met	missense_variant	Exon 21 of 38	ENST00000382722.10	NP_758952.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA2D4	ENST00000382722.10 link	c.2035C>A	p.Leu679Met	missense_variant	Exon 21 of 38	1	NM_172364.5	ENSP00000372169.4
CACNA2D4	ENST00000586184.5 link	c.2035C>A	p.Leu679Met	missense_variant	Exon 21 of 37	5		ENSP00000465060.1
CACNA2D4	ENST00000587995.5 link	c.1960C>A	p.Leu654Met	missense_variant	Exon 20 of 37	5		ENSP00000465372.1
CACNA2D4	ENST00000585708.5 link	c.1843C>A	p.Leu615Met	missense_variant	Exon 21 of 37	5		ENSP00000467697.1
CACNA2D4	ENST00000588077.5 link	c.1843C>A	p.Leu615Met	missense_variant	Exon 21 of 38	5		ENSP00000468530.1
CACNA2D4	ENST00000444595.6 link	n.*281C>A		non_coding_transcript_exon_variant	Exon 21 of 37	1		ENSP00000403371.2
CACNA2D4	ENST00000444595.6 link	n.*281C>A		3_prime_UTR_variant	Exon 21 of 37	1		ENSP00000403371.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461690

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727126

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:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111866

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.;.;.;.;.

Eigen

Benign

0.0044

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.78

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.58

D;D;D;D;D;D

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.5

M;.;.;M;.;.

PhyloP100

0.14

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.71

N;.;.;.;.;.

REVEL

Benign

0.11

Sift

Benign

0.13

T;.;.;.;.;.

Sift4G

Uncertain

0.055

T;D;T;D;T;D

Polyphen

0.98

D;.;.;.;.;.

Vest4

0.38

MutPred

0.48

Gain of loop (P = 0.0502);.;.;Gain of loop (P = 0.0502);.;.;

MVP

0.30

MPC

0.46

ClinPred

0.71

GERP RS

2.5

Varity_R

0.090

gMVP

0.43

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over