rs575583988

Variant names:

• chr12-2593223-TGAG-T
• rs575583988
• NM_000719.7:c.2548_2550delGAG

Your query was ambiguous. Multiple possible variants found:

• chr12-2593223-TGAG-T
• chr12-2593223-TGAG-TGAGGAG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PM4_Supporting BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.2548_2550delGAG​(p.Glu850del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,613,740 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00083 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (4 hom.)
• Consequence: CACNA1C NM_000719.7 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 10.0
• Publications: 7 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: Likely_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000719.7
• PM4: Nonframeshift variant in NON repetitive region in NM_000719.7. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 12-2593223-TGAG-T is Benign according to our data. Variant chr12-2593223-TGAG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 155776.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000827 (126/152336) while in subpopulation AMR AF = 0.00438 (67/15298). AF 95% confidence interval is 0.00354. There are 3 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 126 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	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.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2638_2640delGAG	p.Glu880del	conservative_inframe_deletion	Exon 19 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2713_2715delGAG	p.Glu905del	conservative_inframe_deletion	Exon 20 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2638_2640delGAG	p.Glu880del	conservative_inframe_deletion	Exon 19 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2638_2640delGAG	p.Glu880del	conservative_inframe_deletion	Exon 19 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2638_2640delGAG	p.Glu880del	conservative_inframe_deletion	Exon 19 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2638_2640delGAG	p.Glu880del	conservative_inframe_deletion	Exon 19 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2623_2625delGAG	p.Glu875del	conservative_inframe_deletion	Exon 20 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2623_2625delGAG	p.Glu875del	conservative_inframe_deletion	Exon 20 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2539_2541delGAG	p.Glu847del	conservative_inframe_deletion	Exon 19 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2548_2550delGAG	p.Glu850del	conservative_inframe_deletion	Exon 19 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1155_*1157delGAG		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1155_*1157delGAG		3_prime_UTR_variant	Exon 17 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000583 AC: 145 AN: 248606 AF XY: 0.000690

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000842

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000302 AC: 441 AN: 1461404 Hom.: 4 AF XY: 0.000359 AC XY: 261 AN XY: 726940

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00135 AC: 116 AN: 86120

European-Finnish (FIN) AF: 0.00118 AC: 63 AN: 53388

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5766

European-Non Finnish (NFE) AF: 0.000161 AC: 179 AN: 1111760

Other (OTH) AF: 0.000398 AC: 24 AN: 60366

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74496

African (AFR) AF: 0.0000722 AC: 3 AN: 41580

American (AMR) AF: 0.00438 AC: 67 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000129 Hom.: 0

Bravo AF: 0.000484

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Nov 04, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: PM4:Supporting, BS1 -

Jun 03, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Timothy syndrome Uncertain:1 Benign:1

Aug 14, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP6. -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1 Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2013

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1 Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

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. -

not specified Benign:1

Apr 17, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs575583988; hg19: chr12-2702389;