rs786205771

Positions:

chr12-2584592-GAGA-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.49

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.2407_2409delAAG	p.Lys803del	conservative_inframe_deletion	16/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.2482_2484delAAG	p.Lys828del	conservative_inframe_deletion	17/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.2407_2409delAAG	p.Lys803del	conservative_inframe_deletion	16/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.2407_2409delAAG	p.Lys803del	conservative_inframe_deletion	16/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.2407_2409delAAG	p.Lys803del	conservative_inframe_deletion	16/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.2407_2409delAAG	p.Lys803del	conservative_inframe_deletion	16/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.2392_2394delAAG	p.Lys798del	conservative_inframe_deletion	17/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.2392_2394delAAG	p.Lys798del	conservative_inframe_deletion	17/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.2308_2310delAAG	p.Lys770del	conservative_inframe_deletion	16/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.2317_2319delAAG	p.Lys773del	conservative_inframe_deletion	16/46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.924_926delAAG		non_coding_transcript_exon_variant	14/27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000480911.6 link	n.924_926delAAG		3_prime_UTR_variant	14/27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460892

Hom.:

AF XY:

0.00

AC XY:

AN XY:

726730

show subpopulations

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.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2024

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2024

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

Name

Calibrated prediction

Score

Prediction

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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