rs200602896

Variant names:

• chr12-2457567-G-A
• rs200602896
• NM_000719.7:c.618G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2457567-G-A
• chr12-2457567-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.618G>A​(p.Gly206Gly) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000633 in 1,610,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: CACNA1C NM_000719.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.7660
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.84
• Publications: 0 publications found

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

ENSG00000285734 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 12-2457567-G-A is Benign according to our data. Variant chr12-2457567-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00023 (35/152192) while in subpopulation AMR AF = 0.00164 (25/15282). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.708G>A	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.708G>A	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.708G>A	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.708G>A	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.708G>A	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.708G>A	p.Gly236Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.618G>A	p.Gly206Gly	splice_region_variant, synonymous_variant	Exon 5 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.567G>A	p.Gly189Gly	splice_region_variant, synonymous_variant	Exon 4 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.618G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

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: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000893 AC: 22 AN: 246334 AF XY: 0.000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000506

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1458608 Hom.: 0 Cov.: 30 AF XY: 0.0000551 AC XY: 40 AN XY: 725518

African (AFR) AF: 0.0000300 AC: 1 AN: 33304

American (AMR) AF: 0.000361 AC: 16 AN: 44304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85660

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53364

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1110452

Other (OTH) AF: 0.000116 AC: 7 AN: 60194

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74350

African (AFR) AF: 0.0000965 AC: 4 AN: 41450

American (AMR) AF: 0.00164 AC: 25 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.000291

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000219

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 24, 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. -

Apr 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1C c.618G>A (p.Gly206Gly) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.9e-05 in 246334 control chromosomes (gnomAD), predominantly at a frequency of 0.00051 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 51 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing the Timothy Syndrome phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.618G>A in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: BP4 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CACNA1C-related disorder Benign:1

Aug 24, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Long QT syndrome Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Nov 14, 2023

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	-0.26
CADD	Benign	20
DANN	Benign	0.96
PhyloP100		6.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.77
dbscSNV1_RF	Benign	0.51
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

Other links and lift over

dbSNP: rs200602896; hg19: chr12-2566733;