rs369194462

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000720.4(CACNA1D):​c.6253-11T>C variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.0001366
2

Clinical Significance

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

Conservation

PhyloP100: -0.609
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 ClinVar 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1DNM_000720.4 linkuse as main transcriptc.6253-11T>C splice_polypyrimidine_tract_variant, intron_variant ENST00000288139.11 NP_000711.1
CACNA1DNM_001128840.3 linkuse as main transcriptc.6193-11T>C splice_polypyrimidine_tract_variant, intron_variant ENST00000350061.11 NP_001122312.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1DENST00000288139.11 linkuse as main transcriptc.6253-11T>C splice_polypyrimidine_tract_variant, intron_variant 1 NM_000720.4 ENSP00000288139 P2Q01668-2
CACNA1DENST00000350061.11 linkuse as main transcriptc.6193-11T>C splice_polypyrimidine_tract_variant, intron_variant 1 NM_001128840.3 ENSP00000288133 Q01668-1

Frequencies

GnomAD3 genomes
AF:
0.000237
AC:
36
AN:
152118
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.00106
AC:
267
AN:
251426
Hom.:
2
AF XY:
0.00157
AC XY:
214
AN XY:
135900
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 SAS exome
AF:
0.00866
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.:
9
Cov.:
30
AF XY:
0.000882
AC XY:
641
AN XY:
726710
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00923
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.000249
GnomAD4 genome
AF:
0.000236
AC:
36
AN:
152236
Hom.:
0
Cov.:
32
AF XY:
0.000390
AC XY:
29
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00705
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
Asia WGS
AF:
0.00462
AC:
16
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
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 30, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 30, 2019- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 20, 2018c.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
11
DANN
Benign
0.44

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

LitVar

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

Other links and lift over

dbSNP: rs369194462; hg19: chr3-53845129; API