Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000720.4(CACNA1D):c.6111G>A(p.Pro2037Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,613,936 control chromosomes in the GnomAD database, including 1,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 89 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1008 hom. )

Consequence

CACNA1D
NM_000720.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.01

Publications

9 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=-0.72).

BP6

Variant 3-53810157-G-A is Benign according to our data. Variant chr3-53810157-G-A is described in ClinVar as Benign. ClinVar VariationId is 226477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.01 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0265 (4041/152294) while in subpopulation NFE AF = 0.0374 (2542/68012). AF 95% confidence interval is 0.0362. There are 89 homozygotes in GnomAd4. There are 1930 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 89 AD,AR gene

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.6111G>A	p.Pro2037Pro	synonymous	Exon 48 of 49	NP_000711.1
CACNA1D	NM_001128840.3	MANE Select	c.6051G>A	p.Pro2017Pro	synonymous	Exon 47 of 48	NP_001122312.1
CACNA1D	NM_001128839.3		c.5979G>A	p.Pro1993Pro	synonymous	Exon 45 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.6111G>A	p.Pro2037Pro	synonymous	Exon 48 of 49	ENSP00000288139.3
CACNA1D	ENST00000350061.11	TSL:1 MANE Select	c.6051G>A	p.Pro2017Pro	synonymous	Exon 47 of 48	ENSP00000288133.5
CACNA1D	ENST00000481478.2	TSL:1	c.6111G>A	p.Pro2037Pro	synonymous	Exon 48 of 49	ENSP00000418014.2

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4040

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00637

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0244

Gnomad ASJ

AF:

0.0518

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0246

Gnomad FIN

AF:

0.0436

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0374

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0303

AC:

7617

AN:

251262

AF XY:

0.0316

show subpopulations

Gnomad AFR exome

AF:

0.00585

Gnomad AMR exome

AF:

0.0179

Gnomad ASJ exome

AF:

0.0522

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0419

Gnomad NFE exome

AF:

0.0397

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0349

AC:

51057

AN:

1461642

Hom.:

1008

Cov.:

AF XY:

0.0349

AC XY:

25356

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.00499

AC:

167

AN:

33478

American (AMR)

AF:

0.0187

AC:

835

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0533

AC:

1394

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0237

AC:

2046

AN:

86258

European-Finnish (FIN)

AF:

0.0399

AC:

2124

AN:

53182

Middle Eastern (MID)

AF:

0.0534

AC:

308

AN:

5768

European-Non Finnish (NFE)

AF:

0.0380

AC:

42233

AN:

1112000

Other (OTH)

AF:

0.0323

AC:

1949

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

3085

6170

9255

12340

15425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1564

3128

4692

6256

7820

<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:

0.0265

AC:

4041

AN:

152294

Hom.:

Cov.:

AF XY:

0.0259

AC XY:

1930

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00638

AC:

265

AN:

41566

American (AMR)

AF:

0.0244

AC:

373

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0518

AC:

180

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0251

AC:

121

AN:

4828

European-Finnish (FIN)

AF:

0.0436

AC:

463

AN:

10612

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0374

AC:

2542

AN:

68012

Other (OTH)

AF:

0.0289

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

204

408

611

815

1019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0352

Hom.:

210

Bravo

AF:

0.0251

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0396

EpiControl

AF:

0.0406

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Aldosterone-producing adenoma with seizures and neurological abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.33

(source)

DANN

Benign

0.73

PhyloP100

-5.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

rs34388124

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