rs369194462

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000720.4(CACNA1D):c.6253-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,612,796 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 9 hom. )

Consequence

CACNA1D
NM_000720.4 intron

Scores

Splicing: ADA: 0.0001366

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.609

Publications

0 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=-0.82).

BP6

Variant 3-53811102-T-C is Benign according to our data. Variant chr3-53811102-T-C is described in CliVar as Benign. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53811102-T-C is described in CliVar as Benign. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53811102-T-C is described in CliVar as Benign. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53811102-T-C is described in CliVar as Benign. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53811102-T-C is described in CliVar as Benign. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53811102-T-C is described in CliVar as Benign. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53811102-T-C is described in CliVar as Benign. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53811102-T-C is described in CliVar as Benign. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53811102-T-C is described in CliVar as Benign. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53811102-T-C is described in CliVar as Benign. Clinvar id is 504812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000236 (36/152236) while in subpopulation SAS AF = 0.00705 (34/4822). AF 95% confidence interval is 0.00519. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4 link	c.6253-11T>C		intron_variant	Intron 48 of 48	ENST00000288139.11	NP_000711.1	Q01668-2Q59GD8
CACNA1D	NM_001128840.3 link	c.6193-11T>C		intron_variant	Intron 47 of 47	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.6253-11T>C		intron_variant	Intron 48 of 48	1	NM_000720.4	ENSP00000288139.3		Q01668-2
CACNA1D	ENST00000350061.11 link	c.6193-11T>C		intron_variant	Intron 47 of 47	1	NM_001128840.3	ENSP00000288133.5		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00106

AC:

267

AN:

251426

AF XY:

0.00157

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000559

AC:

817

AN:

1460560

Hom.:

Cov.:

AF XY:

0.000882

AC XY:

641

AN XY:

726710

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00923

AC:

796

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110896

Other (OTH)

AF:

0.000249

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

138

184

230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000236

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00705

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000264

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 30, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 20, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.6253-11T>C in Intron 48 of CACNA1D: This variant is not expected to have clini cal significance because it has been identified in 0.9% (265/30782) of South Asi an chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs369194462). In addition, splice predictions do not predict an impact to splicing and a T>C change at this position does not diverge from th e splice consensus sequence and is therefore unlikely to impact splicing.ACMG/AM P Criteria applied: BS1, BS2, BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.44

PhyloP100

-0.61

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over