NM_000720.4:c.5827_5829delTTC

Variant names:

• chr3-53808664-CCTT-C
• rs72556363
• NM_000720.4:c.5827_5829delTTC

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_000720.4(CACNA1D):​c.5827_5829delTTC​(p.Phe1943del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,608,994 control chromosomes in the GnomAD database, including 26 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (25 hom.)
• Consequence: CACNA1D NM_000720.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 7.78

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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000720.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 3-53808664-CCTT-C is Benign according to our data. Variant chr3-53808664-CCTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 227204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53808664-CCTT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00236 (359/152316) while in subpopulation NFE AF= 0.00431 (293/68018). AF 95% confidence interval is 0.0039. There are 1 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4	c.5827_5829delTTC	p.Phe1943del	conservative_inframe_deletion	Exon 47 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3	c.5767_5769delTTC	p.Phe1923del	conservative_inframe_deletion	Exon 46 of 48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11	c.5827_5829delTTC	p.Phe1943del	conservative_inframe_deletion	Exon 47 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11	c.5767_5769delTTC	p.Phe1923del	conservative_inframe_deletion	Exon 46 of 48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00240 AC: 594 AN: 247542 Hom.: 3 AF XY: 0.00226 AC XY: 303 AN XY: 134188

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000951

Gnomad NFE exome AF: 0.00458

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00445 AC: 6483 AN: 1456678 Hom.: 25 AF XY: 0.00430 AC XY: 3117 AN XY: 724866

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00126

Gnomad4 NFE exome AF: 0.00553

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74470

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00431

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000775 Hom.: 0

Bravo AF: 0.00245

EpiCase AF: 0.00398

EpiControl AF: 0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1D: BS2 -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CACNA1D p.Phe1923del variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs72556363) and ClinVar (classified as likely benign by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics and as benign by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine). The variant was identified in control databases in 673 of 278936 chromosomes (3 homozygous) at a frequency of 0.002413 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 588 of 129052 chromosomes (freq: 0.004556), Other in 15 of 7200 chromosomes (freq: 0.002083), European (Finnish) in 20 of 21356 chromosomes (freq: 0.000937), African in 21 of 24966 chromosomes (freq: 0.000841), Latino in 24 of 35436 chromosomes (freq: 0.000677), Ashkenazi Jewish in 2 of 10368 chromosomes (freq: 0.000193) and South Asian in 3 of 30616 chromosomes (freq: 0.000098), but was not observed in the East Asian population. This variant is an in-frame deletion resulting in the removal of a phenylalanine (phe) residue at codon 1923; the impact of this alteration on CACNA1D protein function is not known. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Aug 09, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Phe1943del in exon 47 of CACNA1D: This variant is not expected to have clinica l significance because it has been identified in 0.4% (285/66318) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs72556363). -

Feb 25, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aldosterone-producing adenoma with seizures and neurological abnormalities Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sinoatrial node dysfunction and deafness;C3809609:Aldosterone-producing adenoma with seizures and neurological abnormalities Benign:1

Dec 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs72556363; hg19: chr3-53842691;