3-53747296-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001128840.3(CACNA1D):​c.3168-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,613,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CACNA1D
NM_001128840.3 splice_region, intron

Scores

2
Splicing: ADA: 0.0005636
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.145
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 3-53747296-C-G is Benign according to our data. Variant chr3-53747296-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 227198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00115 (175/152338) while in subpopulation AFR AF= 0.00411 (171/41574). AF 95% confidence interval is 0.00361. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1DNM_000720.4 linkc.3228-6C>G splice_region_variant, intron_variant Intron 26 of 48 ENST00000288139.11 NP_000711.1 Q01668-2Q59GD8
CACNA1DNM_001128840.3 linkc.3168-6C>G splice_region_variant, intron_variant Intron 25 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.3228-6C>G splice_region_variant, intron_variant Intron 26 of 48 1 NM_000720.4 ENSP00000288139.3 Q01668-2
CACNA1DENST00000350061.11 linkc.3168-6C>G splice_region_variant, intron_variant Intron 25 of 47 1 NM_001128840.3 ENSP00000288133.5 Q01668-1

Frequencies

GnomAD3 genomes
AF:
0.00114
AC:
174
AN:
152220
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000326
AC:
82
AN:
251414
Hom.:
1
AF XY:
0.000250
AC XY:
34
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.00400
Gnomad AMR exome
AF:
0.000376
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000115
AC:
168
AN:
1461522
Hom.:
0
Cov.:
31
AF XY:
0.0000880
AC XY:
64
AN XY:
727110
show subpopulations
Gnomad4 AFR exome
AF:
0.00433
Gnomad4 AMR exome
AF:
0.000335
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.00115
AC:
175
AN:
152338
Hom.:
1
Cov.:
32
AF XY:
0.000993
AC XY:
74
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00411
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000670
Hom.:
0
Bravo
AF:
0.00144

ClinVar

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

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 04, 2025- -
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 27, 2021- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 25, 2017c.3228-6C>G in intron 26 of CACNA1D: This variant is not expected to have clinic al significance because it has been identified in 0.38% (92/24032) of African ch romosomes including 2 homozygotes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org; dbSNP rs72556355). -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 24, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
6.2
DANN
Benign
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00056
dbscSNV1_RF
Benign
0.11
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72556355; hg19: chr3-53781323; API