chr12-2664915-G-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):​c.4323G>A​(p.Thr1441Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,794 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: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -4.35

Publications

1 publications found
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]
CACNA1C Gene-Disease associations (from GenCC):
  • Timothy syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
  • neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
    Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
  • long QT syndrome
    Inheritance: AD Classification: MODERATE Submitted by: ClinGen
  • long QT syndrome 8
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • Brugada syndrome
    Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
  • Brugada syndrome 3
    Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • intellectual disability
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • short QT syndrome
    Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 12-2664915-G-A is Benign according to our data. Variant chr12-2664915-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 308152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-4.35 with no splicing effect.
BS2
High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 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.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.4557G>A p.Thr1519Thr synonymous_variant Exon 37 of 50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.4290G>A p.Thr1430Thr synonymous_variant Exon 34 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.4488G>A p.Thr1496Thr synonymous_variant Exon 36 of 48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.4467G>A p.Thr1489Thr synonymous_variant Exon 37 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.4389G>A p.Thr1463Thr synonymous_variant Exon 35 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.4413G>A p.Thr1471Thr synonymous_variant Exon 35 of 47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.4413G>A p.Thr1471Thr synonymous_variant Exon 35 of 47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.4413G>A p.Thr1471Thr synonymous_variant Exon 35 of 47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.4413G>A p.Thr1471Thr synonymous_variant Exon 35 of 47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.4407G>A p.Thr1469Thr synonymous_variant Exon 36 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.4398G>A p.Thr1466Thr synonymous_variant Exon 36 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.4383G>A p.Thr1461Thr synonymous_variant Exon 36 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.4374G>A p.Thr1458Thr synonymous_variant Exon 35 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.4365G>A p.Thr1455Thr synonymous_variant Exon 35 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.4290G>A p.Thr1430Thr synonymous_variant Exon 34 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.4290G>A p.Thr1430Thr synonymous_variant Exon 34 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.4284G>A p.Thr1428Thr synonymous_variant Exon 34 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.4323G>A p.Thr1441Thr synonymous_variant Exon 35 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.4314G>A p.Thr1438Thr synonymous_variant Exon 35 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.4290G>A p.Thr1430Thr synonymous_variant Exon 34 of 46 ENSP00000507309.1 Q13936-19

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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
GnomAD2 exomes
AF:
0.00000801
AC:
2
AN:
249634
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1461580
Hom.:
0
Cov.:
31
AF XY:
0.0000248
AC XY:
18
AN XY:
727064
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86232
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53402
Middle Eastern (MID)
AF:
0.000347
AC:
2
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000225
AC:
25
AN:
1111786
Other (OTH)
AF:
0.00
AC:
0
AN:
60372
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
2
3
5
6
8
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:
0.0000131
AC:
2
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41462
American (AMR)
AF:
0.0000654
AC:
1
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
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:
0.0000579
Hom.:
0
Bravo
AF:
0.0000264
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Long QT syndrome Benign:1
Nov 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiovascular phenotype Benign:1
Nov 18, 2020
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
-0.86
CADD
Benign
0.11
DANN
Benign
0.71
PhyloP100
-4.3

Splicing

Name
Calibrated prediction
Score
Prediction
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

Other links and lift over

dbSNP: rs753892795; hg19: chr12-2774081; COSMIC: COSV59706336; COSMIC: COSV59706336; API