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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA2D4	NM_172364.5 link	c.3065C>T	p.Pro1022Leu	missense_variant	Exon 35 of 38	ENST00000382722.10	NP_758952.4	Q7Z3S7-1
CACNA2D4	XM_011521041.3 link	c.3002C>T	p.Pro1001Leu	missense_variant	Exon 34 of 36		XP_011519343.1
CACNA2D4	XM_047429897.1 link	c.2993C>T	p.Pro998Leu	missense_variant	Exon 34 of 36		XP_047285853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA2D4	ENST00000382722.10 link	c.3065C>T	p.Pro1022Leu	missense_variant	Exon 35 of 38	1	NM_172364.5	ENSP00000372169.4	Q7Z3S7-1
CACNA2D4	ENST00000586184.5 link	c.3065C>T	p.Pro1022Leu	missense_variant	Exon 35 of 37	5		ENSP00000465060.1	Q7Z3S7-5
CACNA2D4	ENST00000587995.5 link	c.2990C>T	p.Pro997Leu	missense_variant	Exon 34 of 37	5		ENSP00000465372.1	K7EJY1
CACNA2D4	ENST00000585708.5 link	c.2873C>T	p.Pro958Leu	missense_variant	Exon 35 of 37	5		ENSP00000467697.1	Q7Z3S7-6
CACNA2D4	ENST00000588077.5 link	c.2873C>T	p.Pro958Leu	missense_variant	Exon 35 of 38	5		ENSP00000468530.1	Q7Z3S7-4
CACNA2D4	ENST00000536846.6 link	c.503C>T	p.Pro168Leu	missense_variant	Exon 9 of 12	5		ENSP00000468167.1	K7ER98
CACNA2D4	ENST00000538027.6 link	c.500C>T	p.Pro167Leu	missense_variant	Exon 9 of 12	5		ENSP00000443038.2	X6RLY7
CACNA2D4	ENST00000538450.5 link	c.455C>T	p.Pro152Leu	missense_variant	Exon 8 of 11	2		ENSP00000446341.1	B4DVU4
CACNA2D4	ENST00000444595.6 link	n.*1249C>T		non_coding_transcript_exon_variant	Exon 34 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.*258C>T		non_coding_transcript_exon_variant	Exon 12 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.*258C>T		non_coding_transcript_exon_variant	Exon 7 of 10	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000585385.5 link	n.*258C>T		non_coding_transcript_exon_variant	Exon 8 of 11	5		ENSP00000467333.1	K7EIY9
CACNA2D4	ENST00000444595.6 link	n.*1249C>T		3_prime_UTR_variant	Exon 34 of 37	1		ENSP00000403371.2	E7EUE0
CACNA2D4	ENST00000537784.5 link	n.*258C>T		3_prime_UTR_variant	Exon 12 of 15	1		ENSP00000440231.2	X6RLU5
CACNA2D4	ENST00000545595.6 link	n.*258C>T		3_prime_UTR_variant	Exon 7 of 10	1		ENSP00000442329.2	Q7Z3S7-7
CACNA2D4	ENST00000585385.5 link	n.*258C>T		3_prime_UTR_variant	Exon 8 of 11	5		ENSP00000467333.1	K7EIY9

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 11, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal cone dystrophy 4

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

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

T;.;.;.;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.19

MetaRNN

Benign

0.0038

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;.;.;.;.;M;.

PhyloP100

0.63

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.6

D;D;.;.;.;.;.

REVEL

Benign

0.044

Sift

Benign

0.30

T;T;.;.;.;.;.

Sift4G

Benign

0.30

T;T;T;T;T;T;T

Polyphen

0.084

B;B;.;B;.;.;.

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over