rs61741336

Positions:

• chr12-1797466-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0098 (111 hom.)
• Consequence: CACNA2D4 NM_172364.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.634

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D4	NM_172364.5	c.3065C>T	p.Pro1022Leu	missense_variant	35/38	ENST00000382722.10	NP_758952.4
CACNA2D4	XM_011521041.3	c.3002C>T	p.Pro1001Leu	missense_variant	34/36		XP_011519343.1
CACNA2D4	XM_047429897.1	c.2993C>T	p.Pro998Leu	missense_variant	34/36		XP_047285853.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1011 AN: 152194 Hom.: 4 Cov.: 34

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

GnomAD3 exomes AF: 0.00850 AC: 1756 AN: 206662 Hom.: 21 AF XY: 0.00950 AC XY: 1069 AN XY: 112514

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 SAS exome AF: 0.0233

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.: 32 AF XY: 0.0102 AC XY: 7271 AN XY: 710932

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.00467

Gnomad4 ASJ exome AF: 0.00603

Gnomad4 EAS exome AF: 0.0000521

Gnomad4 SAS exome AF: 0.0232

Gnomad4 FIN exome AF: 0.00170

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00800

GnomAD4 genome AF: 0.00663 AC: 1010 AN: 152312 Hom.: 4 Cov.: 34 AF XY: 0.00641 AC XY: 477 AN XY: 74470

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00970

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00910 Hom.: 4

Bravo AF: 0.00659

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00177 AC: 7

ESP6500EA AF: 0.00967 AC: 80

ExAC AF: 0.00730 AC: 874

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2014	- -

Retinal cone dystrophy 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 09, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T;.;.;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
MetaRNN	Benign	0.0038	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;M;.
PrimateAI	Benign	0.27	T
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	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs61741336; hg19: chr12-1906632; COSMIC: COSV99028028; COSMIC: COSV99028028;