12-2668886-A-G

Variant names:

• chr12-2668886-A-G
• rs114898435
• NM_000719.7:c.4624-47A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000719.7(CACNA1C):​c.4624-47A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,299,490 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0098 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.12
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-2668886-A-G is Benign according to our data. Variant chr12-2668886-A-G is described in ClinVar as [Benign]. Clinvar id is 695632.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0098 (1491/152214) while in subpopulation AFR AF = 0.0341 (1414/41524). AF 95% confidence interval is 0.0326. There are 28 homozygotes in GnomAd4. There are 698 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1491 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00977 AC: 1486 AN: 152096 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00251 AC: 623 AN: 248632 AF XY: 0.00204

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00106 AC: 1218 AN: 1147276 Hom.: 23 Cov.: 16 AF XY: 0.000908 AC XY: 532 AN XY: 585822

African (AFR) AF: 0.0352 AC: 961 AN: 27276

American (AMR) AF: 0.00183 AC: 81 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24208

East Asian (EAS) AF: 0.00 AC: 0 AN: 38156

South Asian (SAS) AF: 0.0000876 AC: 7 AN: 79886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.000584 AC: 3 AN: 5138

European-Non Finnish (NFE) AF: 0.0000715 AC: 59 AN: 825066

Other (OTH) AF: 0.00213 AC: 107 AN: 50128

GnomAD4 genome AF: 0.00980 AC: 1491 AN: 152214 Hom.: 28 Cov.: 32 AF XY: 0.00938 AC XY: 698 AN XY: 74428

African (AFR) AF: 0.0341 AC: 1414 AN: 41524

American (AMR) AF: 0.00314 AC: 48 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68006

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00326 Hom.: 3

Bravo AF: 0.0116

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.84
CADD	Benign	0.77
DANN	Benign	0.52
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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: rs114898435; hg19: chr12-2778052;