rs61741336

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_172364.5(CACNA2D4):c.3065C>T(p.Pro1022Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00949 in 1,585,220 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1022P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0066 ( 4 hom., cov: 34)

Exomes 𝑓: 0.0098 ( 111 hom. )

Consequence

CACNA2D4
NM_172364.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.634

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

CACNA2D4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038063228).

BP6

Variant 12-1797466-G-A is Benign according to our data. Variant chr12-1797466-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00663 (1010/152312) while in subpopulation SAS AF = 0.0213 (103/4830). AF 95% confidence interval is 0.018. There are 4 homozygotes in GnomAd4. There are 477 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172364.5. 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
	CACNA2D4	NM_172364.5	MANE Select	c.3065C>T	p.Pro1022Leu	missense	Exon 35 of 38	NP_758952.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA2D4	ENST00000382722.10	TSL:1 MANE Select	c.3065C>T	p.Pro1022Leu	missense	Exon 35 of 38	ENSP00000372169.4
CACNA2D4	ENST00000586184.5	TSL:5	c.3065C>T	p.Pro1022Leu	missense	Exon 35 of 37	ENSP00000465060.1
CACNA2D4	ENST00000587995.5	TSL:5	c.2990C>T	p.Pro997Leu	missense	Exon 34 of 37	ENSP00000465372.1

Frequencies

GnomAD3 genomes

AF:

0.00664

AC:

1011

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00798

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0213

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00972

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00850

AC:

1756

AN:

206662

AF XY:

0.00950

show subpopulations

Gnomad AFR exome

AF:

0.00175

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00534

Gnomad EAS exome

AF:

0.000129

Gnomad FIN exome

AF:

0.00104

Gnomad NFE exome

AF:

0.00927

Gnomad OTH exome

AF:

0.00904

GnomAD4 exome

AF:

0.00979

AC:

14027

AN:

1432908

Hom.:

111

Cov.:

AF XY:

0.0102

AC XY:

7271

AN XY:

710932

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

33042

American (AMR)

AF:

0.00467

AC:

195

AN:

41764

Ashkenazi Jewish (ASJ)

AF:

0.00603

AC:

155

AN:

25722

East Asian (EAS)

AF:

0.0000521

AC:

AN:

38364

South Asian (SAS)

AF:

0.0232

AC:

1925

AN:

82796

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

45380

Middle Eastern (MID)

AF:

0.00821

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0101

AC:

11116

AN:

1100718

Other (OTH)

AF:

0.00800

AC:

475

AN:

59400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

736

1472

2208

2944

3680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

426

852

1278

1704

2130

<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

AF:

0.00663

AC:

1010

AN:

152312

Hom.:

Cov.:

AF XY:

0.00641

AC XY:

477

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41586

American (AMR)

AF:

0.00797

AC:

122

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.0213

AC:

103

AN:

4830

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00970

AC:

660

AN:

68020

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00920

Hom.:

Bravo

AF:

0.00659

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00177

AC:

ESP6500EA

AF:

0.00967

AC:

ExAC

AF:

0.00730

AC:

874

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Retinal cone dystrophy 4 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.15

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.19

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

0.63

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.044

Sift

Benign

0.30

Sift4G

Benign

0.30

Polyphen

0.084

Vest4

0.23

MVP

0.072

MPC

0.14

ClinPred

0.0087

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.048

gMVP

0.50

Mutation Taster

=99/1

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over