chr3-53770462-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000720.4(CACNA1D):c.4014C>T(p.Phe1338Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.031 in 1,613,542 control chromosomes in the GnomAD database, including 1,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 174 hom., cov: 33)

Exomes 𝑓: 0.030 ( 830 hom. )

Consequence

CACNA1D
NM_000720.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.00

Publications

11 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

aldosterone-producing adenoma with seizures and neurological abnormalities
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
sinoatrial node dysfunction and deafness
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

CACNA1D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 3-53770462-C-T is Benign according to our data. Variant chr3-53770462-C-T is described in ClinVar as Benign. ClinVar VariationId is 226475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4 link	c.4014C>T	p.Phe1338Phe	synonymous_variant	Exon 33 of 49	ENST00000288139.11	NP_000711.1	Q01668-2Q59GD8
CACNA1D	NM_001128840.3 link	c.3954C>T	p.Phe1318Phe	synonymous_variant	Exon 32 of 48	ENST00000350061.11	NP_001122312.1	Q01668-1Q59GD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11 link	c.4014C>T	p.Phe1338Phe	synonymous_variant	Exon 33 of 49	1	NM_000720.4	ENSP00000288139.3		Q01668-2
CACNA1D	ENST00000350061.11 link	c.3954C>T	p.Phe1318Phe	synonymous_variant	Exon 32 of 48	1	NM_001128840.3	ENSP00000288133.5		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.0413

AC:

6284

AN:

152130

Hom.:

173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0720

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0431

Gnomad ASJ

AF:

0.0588

Gnomad EAS

AF:

0.00635

Gnomad SAS

AF:

0.0360

Gnomad FIN

AF:

0.00443

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0295

Gnomad OTH

AF:

0.0631

GnomAD2 exomes

AF:

0.0327

AC:

8222

AN:

251494

AF XY:

0.0331

show subpopulations

Gnomad AFR exome

AF:

0.0737

Gnomad AMR exome

AF:

0.0380

Gnomad ASJ exome

AF:

0.0518

Gnomad EAS exome

AF:

0.00767

Gnomad FIN exome

AF:

0.00531

Gnomad NFE exome

AF:

0.0298

Gnomad OTH exome

AF:

0.0366

GnomAD4 exome

AF:

0.0299

AC:

43727

AN:

1461294

Hom.:

830

Cov.:

AF XY:

0.0304

AC XY:

22127

AN XY:

726990

show subpopulations

African (AFR)

AF:

0.0772

AC:

2582

AN:

33464

American (AMR)

AF:

0.0397

AC:

1774

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0497

AC:

1299

AN:

26134

East Asian (EAS)

AF:

0.00494

AC:

196

AN:

39698

South Asian (SAS)

AF:

0.0431

AC:

3715

AN:

86232

European-Finnish (FIN)

AF:

0.00534

AC:

285

AN:

53414

Middle Eastern (MID)

AF:

0.0786

AC:

453

AN:

5766

European-Non Finnish (NFE)

AF:

0.0282

AC:

31331

AN:

1111476

Other (OTH)

AF:

0.0346

AC:

2092

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

2086

4172

6258

8344

10430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1226

2452

3678

4904

6130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0414

AC:

6296

AN:

152248

Hom.:

174

Cov.:

AF XY:

0.0405

AC XY:

3016

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0720

AC:

2991

AN:

41538

American (AMR)

AF:

0.0434

AC:

663

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0588

AC:

204

AN:

3470

East Asian (EAS)

AF:

0.00656

AC:

AN:

5182

South Asian (SAS)

AF:

0.0360

AC:

174

AN:

4828

European-Finnish (FIN)

AF:

0.00443

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0295

AC:

2008

AN:

68008

Other (OTH)

AF:

0.0629

AC:

133

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

315

630

946

1261

1576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0353

Hom.:

493

Bravo

AF:

0.0463

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0377

EpiControl

AF:

0.0380

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 11, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Phe1338Phe in exon 33 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 7.1% (314/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17053501). -

Aldosterone-producing adenoma with seizures and neurological abnormalities

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

5.0

Mutation Taster

=35/65

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over