12-2605095-A-G

Variant names:

• chr12-2605095-A-G
• rs1555878870
• NM_000719.7:c.2975A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.2975A>G​(p.Asn992Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,632 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.27

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11816582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3125A>G	p.Asn1042Ser	missense_variant	Exon 24 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3140A>G	p.Asn1047Ser	missense_variant	Exon 24 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3035A>G	p.Asn1012Ser	missense_variant	Exon 24 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3065A>G	p.Asn1022Ser	missense_variant	Exon 23 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3065A>G	p.Asn1022Ser	missense_variant	Exon 23 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3065A>G	p.Asn1022Ser	missense_variant	Exon 23 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3065A>G	p.Asn1022Ser	missense_variant	Exon 23 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3050A>G	p.Asn1017Ser	missense_variant	Exon 24 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3035A>G	p.Asn1012Ser	missense_variant	Exon 24 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3050A>G	p.Asn1017Ser	missense_variant	Exon 24 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2966A>G	p.Asn989Ser	missense_variant	Exon 23 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2975A>G	p.Asn992Ser	missense_variant	Exon 23 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1582A>G		non_coding_transcript_exon_variant	Exon 21 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1582A>G		3_prime_UTR_variant	Exon 21 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461458 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727028

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Apr 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N992S variant (also known as c.2975A>G), located in coding exon 23 of the CACNA1C gene, results from an A to G substitution at nucleotide position 2975. The asparagine at codon 992 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	-1.9	.;.;.;.;.;.;.;.;.;.;.;N;N;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.070	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.97, 0.034, 0.0020, 0.012, 1.0, 0.78, 1.0, 0.99	.;D;D;B;B;B;D;D;D;B;D;D;D;P;D;D;.;D;D;.;.;.;D
Vest4		0.20
MutPred		0.47		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at A1010 (P = 0.001);Gain of catalytic residue at A1010 (P = 0.001);.;.;.;.;.;.;.;.;.;.;
MVP		0.88
MPC		0.85
ClinPred		0.93	D
GERP RS		4.5
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555878870; hg19: chr12-2714261;