rs145203578

chr3-53702764-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000720.4(CACNA1D):c.1344C>T(p.Ile448=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,168 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: CACNA1D NM_000720.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.447

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 3-53702764-C-T is Benign according to our data. Variant chr3-53702764-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53702764-C-T is described in Lovd as [Benign]. Variant chr3-53702764-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.447 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00108 (165/152284) while in subpopulation NFE AF= 0.00181 (123/68012). AF 95% confidence interval is 0.00155. There are 0 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.1344C>T	p.Ile448=	synonymous_variant	9/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.1344C>T	p.Ile448=	synonymous_variant	9/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.1344C>T	p.Ile448=	synonymous_variant	9/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.1344C>T	p.Ile448=	synonymous_variant	9/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00106 AC: 267 AN: 251454 Hom.: 0 AF XY: 0.00115 AC XY: 156 AN XY: 135912

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00137 AC: 1997 AN: 1461884 Hom.: 3 Cov.: 32 AF XY: 0.00135 AC XY: 982 AN XY: 727240

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00155

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74470

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00107

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00130

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 02, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 02, 2016	p.Ile448Ile in exon 9 of CACNA1D: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.2% (115/66702) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs145203578). -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	4.0
Dann	Benign	0.55

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: rs145203578; hg19: chr3-53736791; COSMIC: COSV55454221; COSMIC: COSV55454221;