rs786205771

Variant names:

• chr12-2584592-GAGA-G
• rs786205771
• NM_000719.7:c.2317_2319delAAG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000719.7(CACNA1C):​c.2317_2319delAAG​(p.Lys773del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.49

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-2584592-GAGA-G is Pathogenic according to our data. Variant chr12-2584592-GAGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2407_2409delAAG	p.Lys803del	conservative_inframe_deletion	Exon 16 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2482_2484delAAG	p.Lys828del	conservative_inframe_deletion	Exon 17 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2407_2409delAAG	p.Lys803del	conservative_inframe_deletion	Exon 16 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2407_2409delAAG	p.Lys803del	conservative_inframe_deletion	Exon 16 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2407_2409delAAG	p.Lys803del	conservative_inframe_deletion	Exon 16 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2407_2409delAAG	p.Lys803del	conservative_inframe_deletion	Exon 16 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2392_2394delAAG	p.Lys798del	conservative_inframe_deletion	Exon 17 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2392_2394delAAG	p.Lys798del	conservative_inframe_deletion	Exon 17 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2308_2310delAAG	p.Lys770del	conservative_inframe_deletion	Exon 16 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	Exon 16 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*924_*926delAAG		non_coding_transcript_exon_variant	Exon 14 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*924_*926delAAG		3_prime_UTR_variant	Exon 14 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460892 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:1

Sep 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.2317_2319del, results in the deletion of 1 amino acid(s) of the CACNA1C protein (p.Lys773del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of CACNA1C-related conditions (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 411734). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jul 12, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2317_2319delAAG variant (also known as p.K773del) is located in coding exon 16 of the CACNA1C gene. This variant results from an in-frame AAG deletion at nucleotide positions 2317 to 2319. This results in the in-frame deletion of a lysine at codon 773. This alteration has been reported in individuals with long QT syndrome and was found to be de novo in one individual (Ambry internal data; external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic for CACNA1C-related long QT syndrome/Timothy syndrome; however, its clinical significance for CACNA1C-related neurodevelopmental disorder is uncertain. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs786205771; hg19: chr12-2693758;