12-2593229-G-A

Variant names:

• chr12-2593229-G-A
• rs759093479
• NM_000719.7:c.2547G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.2547G>A​(p.Glu849Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,588 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: 0.0000075 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.484
• Publications: 2 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-2593229-G-A is Benign according to our data. Variant chr12-2593229-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 527070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.484 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2637G>A	p.Glu879Glu	synonymous_variant	Exon 19 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2712G>A	p.Glu904Glu	synonymous_variant	Exon 20 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2637G>A	p.Glu879Glu	synonymous_variant	Exon 19 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2637G>A	p.Glu879Glu	synonymous_variant	Exon 19 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2637G>A	p.Glu879Glu	synonymous_variant	Exon 19 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2637G>A	p.Glu879Glu	synonymous_variant	Exon 19 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2622G>A	p.Glu874Glu	synonymous_variant	Exon 20 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2622G>A	p.Glu874Glu	synonymous_variant	Exon 20 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2538G>A	p.Glu846Glu	synonymous_variant	Exon 19 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2547G>A	p.Glu849Glu	synonymous_variant	Exon 19 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1154G>A		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1154G>A		3_prime_UTR_variant	Exon 17 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248576 AF XY: 0.0000222

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: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461362 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726914

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111742

Other (OTH) AF: 0.0000331 AC: 2 AN: 60360

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 17, 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	-0.39
CADD	Benign	6.7
DANN	Benign	0.53
PhyloP100		0.48

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

Other links and lift over

dbSNP: rs759093479; hg19: chr12-2702395;