chr12-2585372-C-G

Position:

• chr12-2585372-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_000719.7(CACNA1C):​c.2340-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,452 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CACNA1C NM_000719.7 splice_region, intron
• Scores: Splicing: ADA: 0.001528
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.34

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 12-2585372-C-G is Benign according to our data. Variant chr12-2585372-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 527077.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2340-4C>G		splice_region_variant, intron_variant		ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2340-4C>G		splice_region_variant, intron_variant		ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2340-4C>G		splice_region_variant, intron_variant		5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2340-4C>G		splice_region_variant, intron_variant		1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2430-4C>G		splice_region_variant, intron_variant				ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2340-4C>G		splice_region_variant, intron_variant		5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2340-4C>G		splice_region_variant, intron_variant		5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2505-4C>G		splice_region_variant, intron_variant				ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2340-4C>G		splice_region_variant, intron_variant		5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2430-4C>G		splice_region_variant, intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2430-4C>G		splice_region_variant, intron_variant				ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2430-4C>G		splice_region_variant, intron_variant				ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2430-4C>G		splice_region_variant, intron_variant				ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2415-4C>G		splice_region_variant, intron_variant		5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2415-4C>G		splice_region_variant, intron_variant				ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2340-4C>G		splice_region_variant, intron_variant		1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2340-4C>G		splice_region_variant, intron_variant				ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2331-4C>G		splice_region_variant, intron_variant				ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2340-4C>G		splice_region_variant, intron_variant				ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*947-4C>G		splice_region_variant, intron_variant		5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245518 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133380

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459452 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 725850

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.030		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: rs1157833396; hg19: chr12-2694538;