12-2053330-C-T

Variant names:

• chr12-2053330-C-T
• rs886049148
• NM_000719.7:c.-233C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000719.7(CACNA1C):​c.-233C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000544 in 1,285,850 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: CACNA1C NM_000719.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.00

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=-0.52).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.-233C>T		5_prime_UTR_variant	Exon 1 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.-233C>T		5_prime_UTR_variant	Exon 1 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603	c.-233C>T		5_prime_UTR_variant	Exon 1 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655	c.-233C>T		5_prime_UTR_variant	Exon 1 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454	c.-233C>T		5_prime_UTR_variant	Exon 1 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634	c.-233C>T		5_prime_UTR_variant	Exon 1 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000347598	c.-233C>T		5_prime_UTR_variant	Exon 1 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000327702	c.-233C>T		5_prime_UTR_variant	Exon 1 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617	c.-233C>T		5_prime_UTR_variant	Exon 1 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000335762	c.-233C>T		5_prime_UTR_variant	Exon 1 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399641	c.-233C>T		5_prime_UTR_variant	Exon 1 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000682835	c.-233C>T		5_prime_UTR_variant	Exon 1 of 47			ENSP00000507282.1
CACNA1C	ENST00000682544.1	c.140-61894C>T		intron_variant	Intron 1 of 49			ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.140-61894C>T		intron_variant	Intron 1 of 47			ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.140-61894C>T		intron_variant	Intron 1 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140-61894C>T		intron_variant	Intron 1 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140-61894C>T		intron_variant	Intron 1 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140-61894C>T		intron_variant	Intron 1 of 46			ENSP00000506882.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000441 AC: 5 AN: 1133684 Hom.: 0 Cov.: 32 AF XY: 0.00000184 AC XY: 1 AN XY: 543112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000669

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000423

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Timothy syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.85

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886049148; hg19: chr12-2162496;