chr3-53727013-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000720.4(CACNA1D):​c.2281+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CACNA1D
NM_000720.4 intron

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0860

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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 3-53727013-C-T is Benign according to our data. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53727013-C-T is described in CliVar as Likely_benign. Clinvar id is 504767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1DNM_000720.4 linkc.2281+14C>T intron_variant Intron 16 of 48 ENST00000288139.11 NP_000711.1 Q01668-2Q59GD8
CACNA1DNM_001128840.3 linkc.2221+14C>T intron_variant Intron 15 of 47 ENST00000350061.11 NP_001122312.1 Q01668-1Q59GD8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1DENST00000288139.11 linkc.2281+14C>T intron_variant Intron 16 of 48 1 NM_000720.4 ENSP00000288139.3 Q01668-2
CACNA1DENST00000350061.11 linkc.2221+14C>T intron_variant Intron 15 of 47 1 NM_001128840.3 ENSP00000288133.5 Q01668-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000795
AC:
2
AN:
251456
AF XY:
0.00000736
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:
0.0000123
AC:
18
AN:
1461784
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727220
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53388
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000126
AC:
14
AN:
1111944
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000329
AC:
5
AN:
152162
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74326
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41440
American (AMR)
AF:
0.000131
AC:
2
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4810
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.515
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.0000264

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Oct 27, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

c.2281+14C>T in intron 16 of CACNA1D: This variant is not expected to have clini cal significance because it is not located within the conserved splice consensus sequence. It has been identified in 1/66740 European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373186365). -

not provided Benign:1
Sep 13, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely 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
-0.86
CADD
Benign
2.5
DANN
Benign
0.81
PhyloP100
-0.086

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs373186365; hg19: chr3-53761040; API