12-2053560-T-C

Position:

chr12-2053560-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000719.7(CACNA1C):c.-3T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000037 in 1,593,740 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000040 ( 2 hom. )

Consequence

CACNA1C
NM_000719.7 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.17

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 12-2053560-T-C is Benign according to our data. Variant chr12-2053560-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 872566.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000395 (57/1441684) while in subpopulation MID AF= 0.000871 (5/5738). AF 95% confidence interval is 0.000343. There are 2 homozygotes in gnomad4_exome. There are 34 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.-3T>C		5_prime_UTR_variant	1/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.-3T>C		5_prime_UTR_variant	1/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603 link	c.-3T>C	5_prime_UTR_variant	1/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655 link	c.-3T>C	5_prime_UTR_variant	1/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000406454 link	c.-3T>C	5_prime_UTR_variant	1/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634 link	c.-3T>C	5_prime_UTR_variant	1/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000347598 link	c.-3T>C	5_prime_UTR_variant	1/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000327702 link	c.-3T>C	5_prime_UTR_variant	1/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617 link	c.-3T>C	5_prime_UTR_variant	1/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000335762 link	c.-3T>C	5_prime_UTR_variant	1/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399641 link	c.-3T>C	5_prime_UTR_variant	1/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000682835 link	c.-3T>C	5_prime_UTR_variant	1/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482 link	c.-3T>C	5_prime_UTR_variant	1/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682544.1 link	c.140-61664T>C	intron_variant				ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000683824.1 link	c.140-61664T>C	intron_variant				ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000682462.1 link	c.140-61664T>C	intron_variant				ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.140-61664T>C	intron_variant				ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.140-61664T>C	intron_variant				ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.140-61664T>C	intron_variant				ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000480911.6 link	n.-3T>C	non_coding_transcript_exon_variant	1/27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000480911.6 link	n.-3T>C	5_prime_UTR_variant	1/27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000344100.7 link	c.-3T>C	upstream_gene_variant		1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000399638.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000399606.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.-3T>C	upstream_gene_variant		1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.-3T>C	upstream_gene_variant				ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399644.5 link	c.-3T>C	upstream_gene_variant		1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682686.1 link	c.-3T>C	upstream_gene_variant				ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152056

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000504

AC:

AN:

218332

Hom.:

AF XY:

0.0000678

AC XY:

AN XY:

117980

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000326

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000227

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000308

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.0000395

AC:

AN:

1441684

Hom.:

Cov.:

AF XY:

0.0000475

AC XY:

AN XY:

715324

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000238

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000263

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74274

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2021

This variant is associated with the following publications: (PMID: 26582918, 27535533) -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2024

This alteration is classified as 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

-0.51

CADD

Benign

DANN

Benign

0.79

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