chr3-53810156-C-T

Position:

• chr3-53810156-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000350061.11(CACNA1D):​c.6050C>T​(p.Pro2017Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P2017P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA1D ENST00000350061.11 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.22

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.36280096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.6110C>T	p.Pro2037Leu	missense_variant	48/49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.6050C>T	p.Pro2017Leu	missense_variant	47/48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.6110C>T	p.Pro2037Leu	missense_variant	48/49	1	NM_000720.4	ENSP00000288139	P2
CACNA1D	ENST00000350061.11	c.6050C>T	p.Pro2017Leu	missense_variant	47/48	1	NM_001128840.3	ENSP00000288133

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461670 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 31, 2016

The p.Pro2037Leu variant in CACNA1D has not been previously reported in individu als with hearing loss or in large population studies. Computational prediction t ools and conservation analyses suggest that the p.Pro2037Leu variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. In summary, the clinical significance of the p.Pro2037Leu variant i s uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;.;.;.;.;.
Eigen	Benign	0.088
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.91	D;D;.;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.4	.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.3	.;D;.;D;D;.;D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	.;D;.;D;D;.;D
Sift4G	Uncertain	0.0040	.;D;.;D;D;.;D
Polyphen		0.61, 0.82, 0.89	.;P;P;P;.;.;P
Vest4		0.58, 0.58, 0.61
MutPred		0.56		.;Gain of glycosylation at S2022 (P = 0.0322);.;.;.;.;.;
MVP		0.35
MPC		0.49
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.52
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs876657749; hg19: chr3-53844183; COSMIC: COSV99860083; COSMIC: COSV99860083;