rs72556360

chr3-53769994-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000720.4(CACNA1D):c.3952C>T(p.Pro1318Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00594 in 1,613,132 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (40 hom.)
• Consequence: CACNA1D NM_000720.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.60

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA1D
• BP4: Computational evidence support a benign effect (MetaRNN=0.0057592094).
• BP6: Variant 3-53769994-C-T is Benign according to our data. Variant chr3-53769994-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53769994-C-T is described in Lovd as [Benign]. Variant chr3-53769994-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00513 (781/152304) while in subpopulation NFE AF= 0.00536 (365/68034). AF 95% confidence interval is 0.00491. There are 6 homozygotes in gnomad4. There are 461 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4	c.3952C>T	p.Pro1318Ser	missense_variant	32/49	ENST00000288139.11
CACNA1D	NM_001128840.3	c.3892C>T	p.Pro1298Ser	missense_variant	31/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11	c.3952C>T	p.Pro1318Ser	missense_variant	32/49	1	NM_000720.4	P2
CACNA1D	ENST00000350061.11	c.3892C>T	p.Pro1298Ser	missense_variant	31/48	1	NM_001128840.3

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 781 AN: 152186 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0295

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00536

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00519 AC: 1305 AN: 251464 Hom.: 10 AF XY: 0.00514 AC XY: 698 AN XY: 135904

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.0268

Gnomad NFE exome AF: 0.00543

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00603 AC: 8803 AN: 1460828 Hom.: 40 Cov.: 30 AF XY: 0.00592 AC XY: 4306 AN XY: 726828

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.0243

Gnomad4 NFE exome AF: 0.00630

Gnomad4 OTH exome AF: 0.00550

GnomAD4 genome AF: 0.00513 AC: 781 AN: 152304 Hom.: 6 Cov.: 33 AF XY: 0.00619 AC XY: 461 AN XY: 74472

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0295

Gnomad4 NFE AF: 0.00536

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00533 Hom.: 6

Bravo AF: 0.00345

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00481 AC: 584

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CACNA1D: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2019	This variant is associated with the following publications: (PMID: 26842699) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro1318Ser in exon 32 of CACNA1D: This variant is not expected to have clinical significance because it has been identified in 0.5% (39/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs72556360). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

CACNA1D-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	23
Dann	Benign	0.19
DEOGEN2	Uncertain	0.43	T;.;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T;.;T;D
MetaRNN	Benign	0.0058	T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	-0.23	N;.;.;.;.
MutationTaster	Benign	0.58	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.26	N;.;.;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.90	T;.;.;T;T
Sift4G	Benign	0.91	T;.;.;T;T
Polyphen		0.0010	B;.;B;B;B
Vest4		0.36
MVP		0.81
MPC		0.81
ClinPred		0.021	T
GERP RS		5.9
Varity_R		0.077
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72556360; hg19: chr3-53804021; COSMIC: COSV55448703; COSMIC: COSV55448703;