12-2668602-A-G

Variant names:

• chr12-2668602-A-G
• rs6489375
• NM_000719.7:c.4624-331A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000719.7(CACNA1C):​c.4624-331A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 255,408 control chromosomes in the GnomAD database, including 69,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (37135 hom., cov: 31)
  • Exomes 𝑓: 0.78 (32420 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.14

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-AS2 (HGNC:):

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-2668602-A-G is Benign according to our data. Variant chr12-2668602-A-G is described in ClinVar as [Benign]. Clinvar id is 673266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4624-331A>G		intron_variant	Intron 37 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4624-331A>G		intron_variant	Intron 37 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4624-331A>G		intron_variant	Intron 37 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4624-331A>G		intron_variant	Intron 37 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4858-331A>G		intron_variant	Intron 39 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4624-331A>G		intron_variant	Intron 37 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4591-331A>G		intron_variant	Intron 36 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4789-331A>G		intron_variant	Intron 38 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4768-331A>G		intron_variant	Intron 39 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4690-331A>G		intron_variant	Intron 37 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4624-331A>G		intron_variant	Intron 37 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4624-331A>G		intron_variant	Intron 37 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4714-331A>G		intron_variant	Intron 37 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4714-331A>G		intron_variant	Intron 37 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4714-331A>G		intron_variant	Intron 37 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4714-331A>G		intron_variant	Intron 37 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4708-331A>G		intron_variant	Intron 38 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4699-331A>G		intron_variant	Intron 38 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4684-331A>G		intron_variant	Intron 38 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4624-331A>G		intron_variant	Intron 37 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4624-331A>G		intron_variant	Intron 37 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4624-331A>G		intron_variant	Intron 37 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4675-331A>G		intron_variant	Intron 37 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4666-331A>G		intron_variant	Intron 37 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4591-331A>G		intron_variant	Intron 36 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4591-331A>G		intron_variant	Intron 36 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4585-331A>G		intron_variant	Intron 36 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4624-331A>G		intron_variant	Intron 37 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4624-331A>G		intron_variant	Intron 37 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4624-331A>G		intron_variant	Intron 37 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4624-331A>G		intron_variant	Intron 37 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4624-331A>G		intron_variant	Intron 37 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4615-331A>G		intron_variant	Intron 37 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4591-331A>G		intron_variant	Intron 36 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99518 AN: 151942 Hom.: 37137 Cov.: 31

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.825

Gnomad OTH AF: 0.677

GnomAD4 exome AF: 0.779 AC: 80551 AN: 103348 Hom.: 32420 Cov.: 0 AF XY: 0.785 AC XY: 41441 AN XY: 52820

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.754

Gnomad4 ASJ exome AF: 0.814

Gnomad4 EAS exome AF: 0.584

Gnomad4 SAS exome AF: 0.846

Gnomad4 FIN exome AF: 0.852

Gnomad4 NFE exome AF: 0.819

Gnomad4 OTH exome AF: 0.766

GnomAD4 genome AF: 0.655 AC: 99527 AN: 152060 Hom.: 37135 Cov.: 31 AF XY: 0.659 AC XY: 49033 AN XY: 74354

Gnomad4 AFR AF: 0.268

Gnomad4 AMR AF: 0.715

Gnomad4 ASJ AF: 0.820

Gnomad4 EAS AF: 0.623

Gnomad4 SAS AF: 0.845

Gnomad4 FIN AF: 0.857

Gnomad4 NFE AF: 0.825

Gnomad4 OTH AF: 0.678

Alfa AF: 0.733 Hom.: 7386

Bravo AF: 0.624

Asia WGS AF: 0.707 AC: 2455 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.096
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6489375; hg19: chr12-2777768;