3-53808712-C-T

Position:

• chr3-53808712-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_001128840.3(CACNA1D):​c.5813C>T​(p.Pro1938Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,609,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CACNA1D NM_001128840.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 2.63

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]

CACNA1D (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 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 6.6073 (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=0.07130602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.5873C>T	p.Pro1958Leu	missense_variant	47/49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.5813C>T	p.Pro1938Leu	missense_variant	46/48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.5873C>T	p.Pro1958Leu	missense_variant	47/49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.5813C>T	p.Pro1938Leu	missense_variant	46/48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000444 AC: 11 AN: 247672 Hom.: 0 AF XY: 0.0000298 AC XY: 4 AN XY: 134276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000275 AC: 40 AN: 1456992 Hom.: 0 Cov.: 31 AF XY: 0.0000221 AC XY: 16 AN XY: 725040

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 24, 2023	BP4, PP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1958 of the CACNA1D protein (p.Pro1958Leu). This variant is present in population databases (rs770886605, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. ClinVar contains an entry for this variant (Variation ID: 505106). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2024	Variant summary: CACNA1D c.5873C>T (p.Pro1958Leu) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain (IPR031688) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 247672 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CACNA1D causing Sinoatrial Node Dysfunction And Deafness, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5873C>T in individuals affected with Sinoatrial Node Dysfunction And Deafness and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 505106). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 20, 2016	p.Pro1958Leu in exon 47 of CACNA1D: This variant is not expected to have clinica l significance due to a lack of conservation across species, including mammals. Of note, 8 mammals have a leucine (Leu) at this position despite high nearby ami no acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. This variant has been identified in 1/8586 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs770886605). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 07, 2020	DNA sequence analysis of the CACNA1D gene demonstrated a sequence change, c.5873C>T, in exon 47 that results in an amino acid change, p.Pro1958Leu. This sequence change does not appear to have been previously described in patients with CACNA1D-related disorders and has has been described in the gnomAD database with a low population frequency of 0.0044% (dbSNP rs770886605). The p.Pro1958Leu change affects a moderately conserved amino acid residue located in a domain of the CACNA1D protein that is not known to be functional. The p.Pro1958Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.15
DEOGEN2	Benign	0.11	.;T;.;.;.;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.78	T;T;.;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.071	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	.;L;.;.;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.76	.;N;.;N;N;.;N
REVEL	Benign	0.15
Sift	Benign	1.0	.;T;.;T;T;.;T
Sift4G	Benign	0.14	.;T;.;T;T;.;T
Polyphen		0.0, 0.011	.;B;B;B;.;.;B
Vest4		0.23, 0.22, 0.23
MutPred		0.14		.;Gain of glycosylation at S1933 (P = 0.0024);.;.;.;.;.;
MVP		0.28
MPC		0.38
ClinPred		0.021	T
GERP RS		3.9
Varity_R		0.027
gMVP		0.37

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: rs770886605; hg19: chr3-53842739;