12-2053536-T-G

Position:

• chr12-2053536-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000719.7(CACNA1C):​c.-27T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,352 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: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.594

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 12-2053536-T-G is Benign according to our data. Variant chr12-2053536-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 385645.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.-27T>G		5_prime_UTR_variant	1/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.-27T>G		5_prime_UTR_variant	1/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603	c.-27T>G		5_prime_UTR_variant	1/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655	c.-27T>G		5_prime_UTR_variant	1/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454	c.-27T>G		5_prime_UTR_variant	1/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634	c.-27T>G		5_prime_UTR_variant	1/47	5		ENSP00000382542.2
CACNA1C	ENST00000347598	c.-27T>G		5_prime_UTR_variant	1/49	1		ENSP00000266376.6
CACNA1C	ENST00000327702	c.-27T>G		5_prime_UTR_variant	1/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617	c.-27T>G		5_prime_UTR_variant	1/48	5		ENSP00000382526.1
CACNA1C	ENST00000335762	c.-27T>G		5_prime_UTR_variant	1/48	5		ENSP00000336982.5
CACNA1C	ENST00000399641	c.-27T>G		5_prime_UTR_variant	1/47	1		ENSP00000382549.1
CACNA1C	ENST00000682835	c.-27T>G		5_prime_UTR_variant	1/47			ENSP00000507282.1
CACNA1C	ENST00000683482	c.-27T>G		5_prime_UTR_variant	1/47			ENSP00000507169.1
CACNA1C	ENST00000682544.1	c.140-61688T>G		intron_variant				ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.140-61688T>G		intron_variant				ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.140-61688T>G		intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140-61688T>G		intron_variant				ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140-61688T>G		intron_variant				ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140-61688T>G		intron_variant				ENSP00000506882.1
CACNA1C	ENST00000344100.7	c.-27T>G		upstream_gene_variant		1		ENSP00000341092.3
CACNA1C	ENST00000399638.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382547.1
CACNA1C	ENST00000399606.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.-27T>G		upstream_gene_variant		1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.-27T>G		upstream_gene_variant				ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382510.1
CACNA1C	ENST00000399644.5	c.-27T>G		upstream_gene_variant		1		ENSP00000382552.1
CACNA1C	ENST00000682686.1	c.-27T>G		upstream_gene_variant				ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.-27T>G		upstream_gene_variant		5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000509 AC: 1 AN: 196360 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 105716

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: 0.0000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424352 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 705594

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: 9.15e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.80

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs776331800; hg19: chr12-2162702;