12-2512926-C-G

Position:

• chr12-2512926-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000719.7(CACNA1C):​c.1332C>G​(p.Ala444Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,459,598 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 (★). Synonymous variant affecting the same amino acid position (i.e. A444A) has been classified as 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: -2.58

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 12-2512926-C-G is Benign according to our data. Variant chr12-2512926-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2080037.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1422C>G	p.Ala474Ala	synonymous_variant	9/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1332C>G	p.Ala444Ala	synonymous_variant	9/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1422C>G	p.Ala474Ala	synonymous_variant	9/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1332C>G	p.Ala444Ala	synonymous_variant	9/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1332C>G	p.Ala444Ala	synonymous_variant	9/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1332C>G	p.Ala444Ala	synonymous_variant	9/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1422C>G	p.Ala474Ala	synonymous_variant	9/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1422C>G	p.Ala474Ala	synonymous_variant	9/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1422C>G	p.Ala474Ala	synonymous_variant	9/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1422C>G	p.Ala474Ala	synonymous_variant	9/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1332C>G	p.Ala444Ala	synonymous_variant	9/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1332C>G	p.Ala444Ala	synonymous_variant	9/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1323C>G	p.Ala441Ala	synonymous_variant	9/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1332C>G	p.Ala444Ala	synonymous_variant	9/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.1113+19540C>G		intron_variant		5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000326 AC: 8 AN: 245250 Hom.: 0 AF XY: 0.0000376 AC XY: 5 AN XY: 132924

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: 0.000187

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1459598 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 725796

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: 0.000244

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.20
DANN	Benign	0.75

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: rs202027411; hg19: chr12-2622092;