NM_000719.7:c.4656C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):​c.4656C>T​(p.Ser1552Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,898 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

2

Clinical Significance

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

Conservation

PhyloP100: -0.281

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]
ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)
CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.28).
BP6
Variant 12-2668965-C-T is Benign according to our data. Variant chr12-2668965-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1535961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.281 with no splicing effect.
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 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.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.4890C>T p.Ser1630Ser synonymous_variant Exon 40 of 50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.4623C>T p.Ser1541Ser synonymous_variant Exon 37 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.4821C>T p.Ser1607Ser synonymous_variant Exon 39 of 48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.4800C>T p.Ser1600Ser synonymous_variant Exon 40 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.4722C>T p.Ser1574Ser synonymous_variant Exon 38 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.4746C>T p.Ser1582Ser synonymous_variant Exon 38 of 47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.4746C>T p.Ser1582Ser synonymous_variant Exon 38 of 47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.4746C>T p.Ser1582Ser synonymous_variant Exon 38 of 47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.4746C>T p.Ser1582Ser synonymous_variant Exon 38 of 47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.4740C>T p.Ser1580Ser synonymous_variant Exon 39 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.4731C>T p.Ser1577Ser synonymous_variant Exon 39 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.4716C>T p.Ser1572Ser synonymous_variant Exon 39 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.4707C>T p.Ser1569Ser synonymous_variant Exon 38 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.4698C>T p.Ser1566Ser synonymous_variant Exon 38 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.4623C>T p.Ser1541Ser synonymous_variant Exon 37 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.4623C>T p.Ser1541Ser synonymous_variant Exon 37 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.4617C>T p.Ser1539Ser synonymous_variant Exon 37 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.4656C>T p.Ser1552Ser synonymous_variant Exon 38 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.4647C>T p.Ser1549Ser synonymous_variant Exon 38 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.4623C>T p.Ser1541Ser synonymous_variant Exon 37 of 46 ENSP00000507309.1 Q13936-19

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000120
AC:
3
AN:
250646
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461728
Hom.:
0
Cov.:
30
AF XY:
0.00000825
AC XY:
6
AN XY:
727174
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33478
American (AMR)
AF:
0.00
AC:
0
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:
0.00
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111872
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74326
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41446
American (AMR)
AF:
0.00
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
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:
0.0000712
Hom.:
0
Bravo
AF:
0.0000227

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
Mar 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiovascular phenotype Benign:1
Dec 21, 2024
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
-0.28
CADD
Benign
11
DANN
Benign
0.83
PhyloP100
-0.28
Mutation Taster
=89/11
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: rs372600490; hg19: chr12-2778131; COSMIC: COSV100217216; API