12-2668895-C-G

Variant names:

• chr12-2668895-C-G
• rs58893912
• NM_000719.7:c.4624-38C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000719.7(CACNA1C):​c.4624-38C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,420,956 control chromosomes in the GnomAD database, including 2,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (1250 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (1067 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.357
• Publications: 1 publications found

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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-2668895-C-G is Benign according to our data. Variant chr12-2668895-C-G is described in ClinVar as [Benign]. Clinvar id is 1231358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4624-38C>G		intron_variant	Intron 37 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4624-38C>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.4624-38C>G		intron_variant	Intron 37 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4624-38C>G		intron_variant	Intron 37 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4858-38C>G		intron_variant	Intron 39 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4624-38C>G		intron_variant	Intron 37 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4591-38C>G		intron_variant	Intron 36 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4789-38C>G		intron_variant	Intron 38 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4768-38C>G		intron_variant	Intron 39 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4690-38C>G		intron_variant	Intron 37 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4624-38C>G		intron_variant	Intron 37 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4624-38C>G		intron_variant	Intron 37 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4714-38C>G		intron_variant	Intron 37 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4714-38C>G		intron_variant	Intron 37 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4714-38C>G		intron_variant	Intron 37 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4714-38C>G		intron_variant	Intron 37 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4708-38C>G		intron_variant	Intron 38 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4699-38C>G		intron_variant	Intron 38 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4684-38C>G		intron_variant	Intron 38 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4624-38C>G		intron_variant	Intron 37 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4624-38C>G		intron_variant	Intron 37 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4624-38C>G		intron_variant	Intron 37 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4675-38C>G		intron_variant	Intron 37 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4666-38C>G		intron_variant	Intron 37 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4591-38C>G		intron_variant	Intron 36 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4591-38C>G		intron_variant	Intron 36 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4585-38C>G		intron_variant	Intron 36 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4624-38C>G		intron_variant	Intron 37 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4624-38C>G		intron_variant	Intron 37 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4624-38C>G		intron_variant	Intron 37 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4624-38C>G		intron_variant	Intron 37 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4624-38C>G		intron_variant	Intron 37 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4615-38C>G		intron_variant	Intron 37 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4591-38C>G		intron_variant	Intron 36 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0707 AC: 10758 AN: 152118 Hom.: 1245 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0478

GnomAD2 exomes AF: 0.0183 AC: 4564 AN: 249364 AF XY: 0.0137

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.000897

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000966

Gnomad OTH exome AF: 0.00809

GnomAD4 exome AF: 0.00782 AC: 9927 AN: 1268722 Hom.: 1067 Cov.: 18 AF XY: 0.00673 AC XY: 4312 AN XY: 641056

African (AFR) AF: 0.260 AC: 7705 AN: 29632

American (AMR) AF: 0.0143 AC: 637 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00120 AC: 30 AN: 24968

East Asian (EAS) AF: 0.00 AC: 0 AN: 38738

South Asian (SAS) AF: 0.000583 AC: 48 AN: 82356

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53294

Middle Eastern (MID) AF: 0.0133 AC: 72 AN: 5400

European-Non Finnish (NFE) AF: 0.000590 AC: 552 AN: 935824

Other (OTH) AF: 0.0163 AC: 882 AN: 54026

GnomAD4 genome AF: 0.0709 AC: 10788 AN: 152234 Hom.: 1250 Cov.: 32 AF XY: 0.0687 AC XY: 5113 AN XY: 74456

African (AFR) AF: 0.246 AC: 10198 AN: 41490

American (AMR) AF: 0.0265 AC: 405 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68026

Other (OTH) AF: 0.0473 AC: 100 AN: 2114

Alfa AF: 0.00658 Hom.: 15

Bravo AF: 0.0835

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.48
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs58893912; hg19: chr12-2778061;