12-2605118-C-T

Variant names:

• chr12-2605118-C-T
• rs1298754627
• NM_000719.7:c.2998C>T

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.2998C>T​(p.Leu1000Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000123 in 1,461,580 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: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.04

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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 12-2605118-C-T is Benign according to our data. Variant chr12-2605118-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3483945.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3148C>T	p.Leu1050Leu	synonymous_variant	Exon 24 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3163C>T	p.Leu1055Leu	synonymous_variant	Exon 24 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3058C>T	p.Leu1020Leu	synonymous_variant	Exon 24 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3088C>T	p.Leu1030Leu	synonymous_variant	Exon 23 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3088C>T	p.Leu1030Leu	synonymous_variant	Exon 23 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3088C>T	p.Leu1030Leu	synonymous_variant	Exon 23 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3088C>T	p.Leu1030Leu	synonymous_variant	Exon 23 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3073C>T	p.Leu1025Leu	synonymous_variant	Exon 24 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3058C>T	p.Leu1020Leu	synonymous_variant	Exon 24 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3073C>T	p.Leu1025Leu	synonymous_variant	Exon 24 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2989C>T	p.Leu997Leu	synonymous_variant	Exon 23 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2998C>T	p.Leu1000Leu	synonymous_variant	Exon 23 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1605C>T		non_coding_transcript_exon_variant	Exon 21 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1605C>T		3_prime_UTR_variant	Exon 21 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249244 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135216

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: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461580 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727096

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: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Benign:1

Jul 30, 2024

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	-0.28
CADD	Benign	12
DANN	Benign	0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs1298754627; hg19: chr12-2714284;