chr3-53810217-A-G

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.6171A>G​(p.Thr2057Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,860 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 16 hom., cov: 32)
Exomes 𝑓: 0.00075 ( 13 hom. )

Consequence

CACNA1D
NM_000720.4 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -0.0600

Publications

2 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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
Variant 3-53810217-A-G is Benign according to our data. Variant chr3-53810217-A-G is described in ClinVar as [Benign]. Clinvar id is 504770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.06 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00702 (1069/152246) while in subpopulation AFR AF = 0.0235 (977/41530). AF 95% confidence interval is 0.0223. There are 16 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1DNM_000720.4 linkc.6171A>G p.Thr2057Thr synonymous_variant Exon 48 of 49 ENST00000288139.11 NP_000711.1 Q01668-2Q59GD8
CACNA1DNM_001128840.3 linkc.6111A>G p.Thr2037Thr synonymous_variant Exon 47 of 48 ENST00000350061.11 NP_001122312.1 Q01668-1Q59GD8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1DENST00000288139.11 linkc.6171A>G p.Thr2057Thr synonymous_variant Exon 48 of 49 1 NM_000720.4 ENSP00000288139.3 Q01668-2
CACNA1DENST00000350061.11 linkc.6111A>G p.Thr2037Thr synonymous_variant Exon 47 of 48 1 NM_001128840.3 ENSP00000288133.5 Q01668-1

Frequencies

GnomAD3 genomes
AF:
0.00700
AC:
1065
AN:
152128
Hom.:
16
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0235
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00504
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:
0.000103
Gnomad OTH
AF:
0.00383
GnomAD2 exomes
AF:
0.00200
AC:
502
AN:
251024
AF XY:
0.00148
show subpopulations
Gnomad AFR exome
AF:
0.0247
Gnomad AMR exome
AF:
0.00214
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.000754
AC:
1102
AN:
1461614
Hom.:
13
Cov.:
31
AF XY:
0.000653
AC XY:
475
AN XY:
727120
show subpopulations
African (AFR)
AF:
0.0243
AC:
812
AN:
33480
American (AMR)
AF:
0.00228
AC:
102
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000464
AC:
4
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53144
Middle Eastern (MID)
AF:
0.00156
AC:
9
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000737
AC:
82
AN:
1112008
Other (OTH)
AF:
0.00154
AC:
93
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
72
144
215
287
359
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
30
60
90
120
150
<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:
0.00702
AC:
1069
AN:
152246
Hom.:
16
Cov.:
32
AF XY:
0.00682
AC XY:
508
AN XY:
74456
show subpopulations
African (AFR)
AF:
0.0235
AC:
977
AN:
41530
American (AMR)
AF:
0.00503
AC:
77
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5168
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000103
AC:
7
AN:
68022
Other (OTH)
AF:
0.00379
AC:
8
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
54
108
161
215
269
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00408
Hom.:
3
Bravo
AF:
0.00807
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.000491
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Nov 11, 2019
Genetic Services Laboratory, University of Chicago
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 24, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Thr2057Thr in exon 48 of CACNA1D: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 2.1% (94/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs76868547). -

not provided Benign:2
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 07, 2019
GeneDx
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
-0.63
CADD
Benign
8.5
DANN
Benign
0.64
PhyloP100
-0.060
Mutation Taster
=86/14
polymorphism

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: rs76868547; hg19: chr3-53844244; API