rs199538058

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_000719.7(CACNA1C):​c.5214C>A​(p.Gly1738Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,558 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1738G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -2.60
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-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.39).
BP6
Variant 12-2679566-C-A is Benign according to our data. Variant chr12-2679566-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136632.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr12-2679566-C-A is described in Lovd as [Benign]. Variant chr12-2679566-C-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.6 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00114 (173/152350) while in subpopulation NFE AF= 0.00169 (115/68028). AF 95% confidence interval is 0.00144. There are 1 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 173 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1CNM_000719.7 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 47 ENST00000399655.6 NP_000710.5 Q13936-12
CACNA1CNM_001167623.2 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 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.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 47 5 NM_001167623.2 ENSP00000382512.1 Q13936-37
CACNA1CENST00000399655.6 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 47 1 NM_000719.7 ENSP00000382563.1 Q13936-12
CACNA1CENST00000682544.1 linkc.5448C>A p.Gly1816Gly synonymous_variant Exon 44 of 50 ENSP00000507184.1 A0A804HIR0
CACNA1CENST00000406454.8 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 48 5 ENSP00000385896.3 F5GY28
CACNA1CENST00000399634.6 linkc.5181C>A p.Gly1727Gly synonymous_variant Exon 41 of 47 5 ENSP00000382542.2 E9PDI6
CACNA1CENST00000683824.1 linkc.5379C>A p.Gly1793Gly synonymous_variant Exon 43 of 48 ENSP00000507867.1 A0A804HKC4
CACNA1CENST00000347598.9 linkc.5358C>A p.Gly1786Gly synonymous_variant Exon 44 of 49 1 ENSP00000266376.6 Q13936-11
CACNA1CENST00000344100.7 linkc.5337C>A p.Gly1779Gly synonymous_variant Exon 42 of 47 1 ENSP00000341092.3 Q13936-14
CACNA1CENST00000327702.12 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 48 1 ENSP00000329877.7 A0A0A0MR67
CACNA1CENST00000399617.6 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 48 5 ENSP00000382526.1 A0A0A0MSA1
CACNA1CENST00000682462.1 linkc.5304C>A p.Gly1768Gly synonymous_variant Exon 42 of 47 ENSP00000507105.1 A0A804HIJ8
CACNA1CENST00000683781.1 linkc.5304C>A p.Gly1768Gly synonymous_variant Exon 42 of 47 ENSP00000507434.1 A0A804HJB6
CACNA1CENST00000683840.1 linkc.5304C>A p.Gly1768Gly synonymous_variant Exon 42 of 47 ENSP00000507612.1 A0A804HJR1
CACNA1CENST00000683956.1 linkc.5304C>A p.Gly1768Gly synonymous_variant Exon 42 of 47 ENSP00000506882.1 A0A804HI37
CACNA1CENST00000399638.5 linkc.5298C>A p.Gly1766Gly synonymous_variant Exon 43 of 48 1 ENSP00000382547.1 Q13936-31
CACNA1CENST00000335762.10 linkc.5289C>A p.Gly1763Gly synonymous_variant Exon 43 of 48 5 ENSP00000336982.5 F5H522
CACNA1CENST00000399606.5 linkc.5274C>A p.Gly1758Gly synonymous_variant Exon 43 of 48 1 ENSP00000382515.1 Q13936-30
CACNA1CENST00000399621.5 linkc.5271C>A p.Gly1757Gly synonymous_variant Exon 42 of 47 1 ENSP00000382530.1 Q13936-24
CACNA1CENST00000399637.5 linkc.5271C>A p.Gly1757Gly synonymous_variant Exon 42 of 47 1 ENSP00000382546.1 Q13936-27
CACNA1CENST00000402845.7 linkc.5271C>A p.Gly1757Gly synonymous_variant Exon 42 of 47 1 ENSP00000385724.3 Q13936-13
CACNA1CENST00000399629.5 linkc.5265C>A p.Gly1755Gly synonymous_variant Exon 42 of 47 1 ENSP00000382537.1 Q13936-32
CACNA1CENST00000682336.1 linkc.5256C>A p.Gly1752Gly synonymous_variant Exon 42 of 47 ENSP00000507898.1 A0A804HKE9
CACNA1CENST00000399591.5 linkc.5238C>A p.Gly1746Gly synonymous_variant Exon 41 of 46 1 ENSP00000382500.1 Q13936-29
CACNA1CENST00000399595.5 linkc.5238C>A p.Gly1746Gly synonymous_variant Exon 41 of 46 1 ENSP00000382504.1 Q13936-25
CACNA1CENST00000399649.5 linkc.5232C>A p.Gly1744Gly synonymous_variant Exon 41 of 46 1 ENSP00000382557.1 Q13936-15
CACNA1CENST00000399597.5 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 47 1 ENSP00000382506.1 Q13936-22
CACNA1CENST00000399601.5 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 47 1 ENSP00000382510.1 Q13936-20
CACNA1CENST00000399641.6 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 47 1 ENSP00000382549.1 Q13936-23
CACNA1CENST00000399644.5 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 47 1 ENSP00000382552.1 Q13936-21
CACNA1CENST00000682835.1 linkc.5214C>A p.Gly1738Gly synonymous_variant Exon 42 of 47 ENSP00000507282.1 A0A804HIZ0
CACNA1CENST00000683482.1 linkc.5205C>A p.Gly1735Gly synonymous_variant Exon 42 of 47 ENSP00000507169.1 Q13936-35
CACNA1CENST00000682686.1 linkc.5181C>A p.Gly1727Gly synonymous_variant Exon 41 of 46 ENSP00000507309.1 Q13936-19

Frequencies

GnomAD3 genomes
AF:
0.00114
AC:
173
AN:
152232
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000916
Gnomad ASJ
AF:
0.00893
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000282
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00169
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00127
AC:
313
AN:
247232
Hom.:
0
AF XY:
0.00132
AC XY:
178
AN XY:
134350
show subpopulations
Gnomad AFR exome
AF:
0.000199
Gnomad AMR exome
AF:
0.000553
Gnomad ASJ exome
AF:
0.00701
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000984
Gnomad FIN exome
AF:
0.000280
Gnomad NFE exome
AF:
0.00182
Gnomad OTH exome
AF:
0.00133
GnomAD4 exome
AF:
0.00134
AC:
1965
AN:
1461208
Hom.:
3
Cov.:
31
AF XY:
0.00139
AC XY:
1009
AN XY:
726874
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.000694
Gnomad4 ASJ exome
AF:
0.00713
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000162
Gnomad4 FIN exome
AF:
0.000337
Gnomad4 NFE exome
AF:
0.00145
Gnomad4 OTH exome
AF:
0.00142
GnomAD4 genome
AF:
0.00114
AC:
173
AN:
152350
Hom.:
1
Cov.:
33
AF XY:
0.00105
AC XY:
78
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.000216
Gnomad4 AMR
AF:
0.000915
Gnomad4 ASJ
AF:
0.00893
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000282
Gnomad4 NFE
AF:
0.00169
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00133
Hom.:
0
Bravo
AF:
0.00118
EpiCase
AF:
0.00180
EpiControl
AF:
0.00226

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
May 15, 2015
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CACNA1C: BP4, BP7 -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:3
Oct 01, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 23, 2014
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Long QT syndrome Benign:1
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Nov 27, 2015
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
-0.39
CADD
Benign
0.28
DANN
Benign
0.86

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

LitVar

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

Other links and lift over

dbSNP: rs199538058; hg19: chr12-2788732; API