12-2053561-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000719.7(CACNA1C):c.-2C>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 0.0000125 in 1,594,260 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 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.293

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BS2

High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.-2C>T		5_prime_UTR_variant	Exon 1 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.-2C>T		5_prime_UTR_variant	Exon 1 of 47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000406454 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000347598 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000327702 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000335762 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399641 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000682835 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482 link	c.-2C>T	5_prime_UTR_variant	Exon 1 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682544.1 link	c.140-61663C>T	intron_variant	Intron 1 of 49			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000683824.1 link	c.140-61663C>T	intron_variant	Intron 1 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000682462.1 link	c.140-61663C>T	intron_variant	Intron 1 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.140-61663C>T	intron_variant	Intron 1 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.140-61663C>T	intron_variant	Intron 1 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.140-61663C>T	intron_variant	Intron 1 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000480911.6 link	n.-2C>T	non_coding_transcript_exon_variant	Exon 1 of 27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000480911.6 link	n.-2C>T	5_prime_UTR_variant	Exon 1 of 27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000344100.7 link	c.-2C>T	upstream_gene_variant		1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000399638.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000399606.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.-2C>T	upstream_gene_variant		1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.-2C>T	upstream_gene_variant				ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399644.5 link	c.-2C>T	upstream_gene_variant		1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682686.1 link	c.-2C>T	upstream_gene_variant				ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000183

AC:

AN:

219036

Hom.:

AF XY:

0.0000338

AC XY:

AN XY:

118328

show subpopulations

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:

0.000113

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000132

AC:

AN:

1442156

Hom.:

Cov.:

AF XY:

0.0000210

AC XY:

AN XY:

715568

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:

0.0000970

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000907

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 03, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

May 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-2C>T variant is located in the 5' untranslated region (5’UTR) of the CACNA1C gene. This variant results from a C to T substitution two nucleotides upstream from the first translated codon. This nucleotide position is well conserved in available vertebrate species. According to data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with CACNA1C-related neurodevelopmental disorder is unknown; however, the association of this alteration with CACNA1C-related long QT syndrome or Timothy syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.93

Splicing

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

Other links and lift over