rs200717140

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):​c.2700G>A​(p.Thr900Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,512 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -0.322
Variant links:
Genes affected
CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.3).
BP6
Variant 12-2595910-G-A is Benign according to our data. Variant chr12-2595910-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 456957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.322 with no splicing effect.
BS2
High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 ENST00000399603.6 NP_001161095.1 Q13936-37

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1CENST00000399603.6 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.2790G>A p.Thr930Thr synonymous_variant Exon 20 of 50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.2865G>A p.Thr955Thr synonymous_variant Exon 21 of 48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.2790G>A p.Thr930Thr synonymous_variant Exon 20 of 47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.2790G>A p.Thr930Thr synonymous_variant Exon 20 of 47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.2790G>A p.Thr930Thr synonymous_variant Exon 20 of 47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.2790G>A p.Thr930Thr synonymous_variant Exon 20 of 47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.2775G>A p.Thr925Thr synonymous_variant Exon 21 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.2775G>A p.Thr925Thr synonymous_variant Exon 21 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.2691G>A p.Thr897Thr synonymous_variant Exon 20 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.2700G>A p.Thr900Thr synonymous_variant Exon 20 of 46 ENSP00000507309.1 Q13936-19
CACNA1CENST00000480911.6 linkn.*1307G>A non_coding_transcript_exon_variant Exon 18 of 27 5 ENSP00000437936.2 F5H638
CACNA1CENST00000480911.6 linkn.*1307G>A 3_prime_UTR_variant Exon 18 of 27 5 ENSP00000437936.2 F5H638

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000402
AC:
10
AN:
248998
Hom.:
0
AF XY:
0.0000518
AC XY:
7
AN XY:
135110
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.00
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:
0.0000797
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461422
Hom.:
0
Cov.:
31
AF XY:
0.0000220
AC XY:
16
AN XY:
727030
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000279
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152090
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000709
Hom.:
0
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

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

Submissions by phenotype

Long QT syndrome Benign:1
Nov 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Jun 21, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This 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
-0.30
CADD
Benign
3.7
DANN
Benign
0.75

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

LitVar

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

Other links and lift over

dbSNP: rs200717140; hg19: chr12-2705076; COSMIC: COSV59698322; API