Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000720.4(CACNA1D):c.2760C>T(p.Ser920Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 1,613,234 control chromosomes in the GnomAD database, including 84,650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6327 hom., cov: 33)

Exomes 𝑓: 0.32 ( 78323 hom. )

Consequence

CACNA1D
NM_000720.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.01

Publications

21 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 3-53735452-C-T is Benign according to our data. Variant chr3-53735452-C-T is described in ClinVar as Benign. ClinVar VariationId is 226470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000720.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1D	NM_000720.4	MANE Plus Clinical	c.2760C>T	p.Ser920Ser	synonymous	Exon 21 of 49	NP_000711.1
CACNA1D	NM_001128840.3	MANE Select	c.2700C>T	p.Ser900Ser	synonymous	Exon 20 of 48	NP_001122312.1
CACNA1D	NM_001128839.3		c.2700C>T	p.Ser900Ser	synonymous	Exon 20 of 46	NP_001122311.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1D	ENST00000288139.11	TSL:1 MANE Plus Clinical	c.2760C>T	p.Ser920Ser	synonymous	Exon 21 of 49	ENSP00000288139.3
CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.2700C>T	p.Ser900Ser	synonymous	Exon 20 of 48	ENSP00000288133.5
CACNA1D	ENST00000481478.2	TSL:1	c.2760C>T	p.Ser920Ser	synonymous	Exon 21 of 49	ENSP00000418014.2

Frequencies

GnomAD3 genomes

AF:

0.259

AC:

39384

AN:

152078

Hom.:

6324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0658

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.373

Gnomad EAS

AF:

0.213

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.362

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.348

Gnomad OTH

AF:

0.273

GnomAD2 exomes

AF:

0.302

AC:

75995

AN:

251442

AF XY:

0.303

show subpopulations

Gnomad AFR exome

AF:

0.0594

Gnomad AMR exome

AF:

0.322

Gnomad ASJ exome

AF:

0.371

Gnomad EAS exome

AF:

0.217

Gnomad FIN exome

AF:

0.369

Gnomad NFE exome

AF:

0.348

Gnomad OTH exome

AF:

0.325

GnomAD4 exome

AF:

0.322

AC:

471051

AN:

1461038

Hom.:

78323

Cov.:

AF XY:

0.321

AC XY:

233045

AN XY:

726902

show subpopulations

African (AFR)

AF:

0.0542

AC:

1813

AN:

33480

American (AMR)

AF:

0.319

AC:

14280

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.368

AC:

9620

AN:

26132

East Asian (EAS)

AF:

0.206

AC:

8168

AN:

39698

South Asian (SAS)

AF:

0.213

AC:

18345

AN:

86240

European-Finnish (FIN)

AF:

0.362

AC:

19330

AN:

53366

Middle Eastern (MID)

AF:

0.267

AC:

1541

AN:

5768

European-Non Finnish (NFE)

AF:

0.341

AC:

379255

AN:

1111258

Other (OTH)

AF:

0.310

AC:

18699

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

17730

35461

53191

70922

88652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11960

23920

35880

47840

59800

<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:

0.259

AC:

39398

AN:

152196

Hom.:

6327

Cov.:

AF XY:

0.259

AC XY:

19286

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0656

AC:

2729

AN:

41570

American (AMR)

AF:

0.302

AC:

4624

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.373

AC:

1296

AN:

3472

East Asian (EAS)

AF:

0.213

AC:

1101

AN:

5164

South Asian (SAS)

AF:

0.219

AC:

1058

AN:

4830

European-Finnish (FIN)

AF:

0.362

AC:

3826

AN:

10572

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.348

AC:

23646

AN:

67972

Other (OTH)

AF:

0.271

AC:

573

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1409

2817

4226

5634

7043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

386

772

1158

1544

1930

<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:

0.319

Hom.:

7214

Bravo

AF:

0.245

Asia WGS

AF:

0.188

AC:

653

AN:

3478

EpiCase

AF:

0.327

EpiControl

AF:

0.333

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Aldosterone-producing adenoma with seizures and neurological abnormalities (2)

not provided (2)

Sinoatrial node dysfunction and deafness (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.86

(source)

DANN

Benign

0.67

PhyloP100

-1.0

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over