12-2606655-G-T

Variant names:

• chr12-2606655-G-T
• rs758461435
• NM_000719.7:c.3201G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000719.7(CACNA1C):​c.3201G>T​(p.Ala1067Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A1067A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 0 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]

CACNA1C-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP7: Synonymous conserved (PhyloP=-1.34 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3351G>T	p.Ala1117Ala	synonymous_variant	Exon 26 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3366G>T	p.Ala1122Ala	synonymous_variant	Exon 26 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3261G>T	p.Ala1087Ala	synonymous_variant	Exon 26 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3291G>T	p.Ala1097Ala	synonymous_variant	Exon 25 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3291G>T	p.Ala1097Ala	synonymous_variant	Exon 25 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3291G>T	p.Ala1097Ala	synonymous_variant	Exon 25 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3291G>T	p.Ala1097Ala	synonymous_variant	Exon 25 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3276G>T	p.Ala1092Ala	synonymous_variant	Exon 26 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3261G>T	p.Ala1087Ala	synonymous_variant	Exon 26 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3276G>T	p.Ala1092Ala	synonymous_variant	Exon 26 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3192G>T	p.Ala1064Ala	synonymous_variant	Exon 25 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3201G>T	p.Ala1067Ala	synonymous_variant	Exon 25 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1808G>T		non_coding_transcript_exon_variant	Exon 23 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1808G>T		3_prime_UTR_variant	Exon 23 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240266 AF XY: 0.00000769

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000918

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456850 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724010

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 84824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109874

Other (OTH) AF: 0.00 AC: 0 AN: 60228

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.13
DANN	Benign	0.74
PhyloP100		-1.3

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: rs758461435; hg19: chr12-2715821;