rs1051978823

Variant names:

• chr12-2679794-C-A
• rs1051978823
• NM_000719.7:c.5442C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2679794-C-A
• chr12-2679794-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000719.7(CACNA1C):​c.5442C>A​(p.Asn1814Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1814S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense, splice_region
• Scores: Splicing: ADA: 0.00004558
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.23
• 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-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07097262).
• BP6: Variant 12-2679794-C-A is Benign according to our data. Variant chr12-2679794-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3232242.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.5442C>A	p.Asn1814Lys	missense splice_region	Exon 42 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5442C>A	p.Asn1814Lys	missense splice_region	Exon 42 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.5586C>A	p.Asn1862Lys	missense splice_region	Exon 44 of 50	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5442C>A	p.Asn1814Lys	missense splice_region	Exon 42 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5442C>A	p.Asn1814Lys	missense splice_region	Exon 42 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.5676C>A	p.Asn1892Lys	missense splice_region	Exon 44 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1403900 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 692524

African (AFR) AF: 0.00 AC: 0 AN: 31816

American (AMR) AF: 0.00 AC: 0 AN: 37008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24880

East Asian (EAS) AF: 0.00 AC: 0 AN: 36292

South Asian (SAS) AF: 0.00 AC: 0 AN: 79834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080296

Other (OTH) AF: 0.00 AC: 0 AN: 58160

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
CardioboostArm	Benign	0.0000014
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.2
DANN	Benign	0.69
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.42	N
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	-2.1	N
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.53	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.089
MutPred		0.38		Gain of ubiquitination at N1862 (P = 0.0085)
MVP		0.38
MPC		0.22
ClinPred		0.050	T
GERP RS		0.65
gMVP		0.25
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.038
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: rs1051978823; hg19: chr12-2788960;