rs35874056

Positions:

• chr3-53702798-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_000720.4(CACNA1D):​c.1378G>A​(p.Gly460Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00053 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G460D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: CACNA1D NM_000720.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 3.15

Genes affected

CACNA1D (HGNC:1391): (calcium voltage-gated channel subunit alpha1 D) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, namely alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1D subunit. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1D. . Gene score misZ 4.5817 (greater than the threshold 3.09). Trascript score misZ 6.6047 (greater than threshold 3.09). GenCC has associacion of gene with sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06262174).
• BP6: Variant 3-53702798-G-A is Benign according to our data. Variant chr3-53702798-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252494.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00042 (64/152220) while in subpopulation NFE AF= 0.000823 (56/68036). AF 95% confidence interval is 0.000651. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.1378G>A	p.Gly460Ser	missense_variant	9/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.1378G>A	p.Gly460Ser	missense_variant	9/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.1378G>A	p.Gly460Ser	missense_variant	9/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.1378G>A	p.Gly460Ser	missense_variant	9/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 251364 Hom.: 0 AF XY: 0.000272 AC XY: 37 AN XY: 135856

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000542 AC: 792 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.000525 AC XY: 382 AN XY: 727232

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000621

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74360

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000420 Hom.: 0

Bravo AF: 0.000397

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 24, 2017	p.Gly460Ser in exon 9 of CACNA1D: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, 23 mammals have a Serine (Ser) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been identified in 46/126 640 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs35874056). ACMG/AMP Criteria applied: BS2 (Richar ds 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 30, 2021	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with a CACNA1D-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 30402224, 30365130) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.86	D;D;T;.;T;D;D;D;D;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.063	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	-0.095	.;N;.;N;N;N;.;.;.;.
MutationTaster	Benign	0.69	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	.;N;.;.;N;N;.;.;N;.
REVEL	Benign	0.28
Sift	Benign	0.34	.;T;.;.;T;T;.;.;T;.
Sift4G	Benign	0.43	.;T;.;.;T;T;.;.;T;.
Polyphen		0.0	.;B;.;B;B;.;.;.;B;.
Vest4		0.16, 0.15, 0.17
MVP		0.58
MPC		0.81
ClinPred		0.043	T
GERP RS		2.2
Varity_R		0.056
gMVP		0.17

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: rs35874056; hg19: chr3-53736825;