rs312480

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000720.4(CACNA1D):c.-54T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 1,294,732 control chromosomes in the GnomAD database, including 520,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.85 ( 54273 hom., cov: 22)

Exomes 𝑓: 0.90 ( 466366 hom. )

Consequence

CACNA1D
NM_000720.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.06

Publications

20 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 3-53495113-T-C is Benign according to our data. Variant chr3-53495113-T-C is described in ClinVar as [Benign]. Clinvar id is 1192642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4 link	c.-54T>C		5_prime_UTR_variant	Exon 1 of 49	ENST00000288139.11	NP_000711.1	Q01668-2Q59GD8
CACNA1D	NM_001128840.3 link	c.-54T>C		5_prime_UTR_variant	Exon 1 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.-54T>C		5_prime_UTR_variant	Exon 1 of 49	1	NM_000720.4	ENSP00000288139.3		Q01668-2
CACNA1D	ENST00000350061.11 link	c.-54T>C		5_prime_UTR_variant	Exon 1 of 48	1	NM_001128840.3	ENSP00000288133.5		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.851

AC:

126082

AN:

148186

Hom.:

54242

Cov.:

show subpopulations

Gnomad AFR

AF:

0.682

Gnomad AMI

AF:

0.921

Gnomad AMR

AF:

0.917

Gnomad ASJ

AF:

0.931

Gnomad EAS

AF:

0.968

Gnomad SAS

AF:

0.948

Gnomad FIN

AF:

0.935

Gnomad MID

AF:

0.955

Gnomad NFE

AF:

0.901

Gnomad OTH

AF:

0.882

GnomAD4 exome

AF:

0.901

AC:

1032691

AN:

1146438

Hom.:

466366

Cov.:

AF XY:

0.904

AC XY:

527739

AN XY:

584020

show subpopulations

African (AFR)

AF:

0.661

AC:

18200

AN:

27538

American (AMR)

AF:

0.940

AC:

40846

AN:

43434

Ashkenazi Jewish (ASJ)

AF:

0.932

AC:

21763

AN:

23350

East Asian (EAS)

AF:

0.974

AC:

35678

AN:

36640

South Asian (SAS)

AF:

0.951

AC:

75931

AN:

79820

European-Finnish (FIN)

AF:

0.929

AC:

45456

AN:

48954

Middle Eastern (MID)

AF:

0.940

AC:

4674

AN:

4972

European-Non Finnish (NFE)

AF:

0.896

AC:

746074

AN:

832714

Other (OTH)

AF:

0.899

AC:

44069

AN:

49016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

3978

7957

11935

15914

19892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.851

AC:

126164

AN:

148294

Hom.:

54273

Cov.:

AF XY:

0.856

AC XY:

61813

AN XY:

72248

show subpopulations

African (AFR)

AF:

0.682

AC:

27072

AN:

39682

American (AMR)

AF:

0.917

AC:

13728

AN:

14972

Ashkenazi Jewish (ASJ)

AF:

0.931

AC:

3222

AN:

3460

East Asian (EAS)

AF:

0.969

AC:

4744

AN:

4898

South Asian (SAS)

AF:

0.948

AC:

4343

AN:

4582

European-Finnish (FIN)

AF:

0.935

AC:

9365

AN:

10016

Middle Eastern (MID)

AF:

0.959

AC:

280

AN:

292

European-Non Finnish (NFE)

AF:

0.901

AC:

60775

AN:

67444

Other (OTH)

AF:

0.882

AC:

1806

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

830

1660

2489

3319

4149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.885

Hom.:

72766

Bravo

AF:

0.838

Asia WGS

AF:

0.924

AC:

3208

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 24, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aldosterone-producing adenoma with seizures and neurological abnormalities

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sinoatrial node dysfunction and deafness

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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

-0.71

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

1.1

PromoterAI

-0.026

Neutral

(source)

Mutation Taster

=300/0

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

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rs312480

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