chr12-2682561-G-C

Variant names:

• chr12-2682561-G-C
• rs764212214
• NM_000719.7:c.5456G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000719.7(CACNA1C):​c.5456G>C​(p.Arg1819Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,962 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1819Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.18
• 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]

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

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41408664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5456G>C	p.Arg1819Pro	missense_variant	Exon 43 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5456G>C	p.Arg1819Pro	missense_variant	Exon 43 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5456G>C	p.Arg1819Pro	missense_variant	Exon 43 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5456G>C	p.Arg1819Pro	missense_variant	Exon 43 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5795G>C	p.Arg1932Pro	missense_variant	Exon 46 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5669G>C	p.Arg1890Pro	missense_variant	Exon 44 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5636G>C	p.Arg1879Pro	missense_variant	Exon 43 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5621G>C	p.Arg1874Pro	missense_variant	Exon 44 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5600G>C	p.Arg1867Pro	missense_variant	Exon 45 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5579G>C	p.Arg1860Pro	missense_variant	Exon 43 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5561G>C	p.Arg1854Pro	missense_variant	Exon 44 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5561G>C	p.Arg1854Pro	missense_variant	Exon 44 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5546G>C	p.Arg1849Pro	missense_variant	Exon 43 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5546G>C	p.Arg1849Pro	missense_variant	Exon 43 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5546G>C	p.Arg1849Pro	missense_variant	Exon 43 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5546G>C	p.Arg1849Pro	missense_variant	Exon 43 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5540G>C	p.Arg1847Pro	missense_variant	Exon 44 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5531G>C	p.Arg1844Pro	missense_variant	Exon 44 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5516G>C	p.Arg1839Pro	missense_variant	Exon 44 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5513G>C	p.Arg1838Pro	missense_variant	Exon 43 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5513G>C	p.Arg1838Pro	missense_variant	Exon 43 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5513G>C	p.Arg1838Pro	missense_variant	Exon 43 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5507G>C	p.Arg1836Pro	missense_variant	Exon 43 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5498G>C	p.Arg1833Pro	missense_variant	Exon 43 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5480G>C	p.Arg1827Pro	missense_variant	Exon 42 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5480G>C	p.Arg1827Pro	missense_variant	Exon 42 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5474G>C	p.Arg1825Pro	missense_variant	Exon 42 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5456G>C	p.Arg1819Pro	missense_variant	Exon 43 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5456G>C	p.Arg1819Pro	missense_variant	Exon 43 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5456G>C	p.Arg1819Pro	missense_variant	Exon 43 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5456G>C	p.Arg1819Pro	missense_variant	Exon 43 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5456G>C	p.Arg1819Pro	missense_variant	Exon 43 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5447G>C	p.Arg1816Pro	missense_variant	Exon 43 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5423G>C	p.Arg1808Pro	missense_variant	Exon 42 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459962 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111324

Other (OTH) AF: 0.00 AC: 0 AN: 60330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Benign	0.000074
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.41	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	0.27	D
PhyloP100		3.2
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Pathogenic	0.67
Sift	Benign	0.037	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T;D;D;D;D;T;D;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.80, 0.0020, 0.56, 0.0, 0.18, 0.28, 0.048, 0.70, 0.17, 0.40, 0.73	.;P;B;P;B;P;B;B;B;P;B;B;P;B;B;.;B;B;.;.;.;P;.
Vest4		0.53
MVP		0.87
MPC		0.28
ClinPred		0.58	D
GERP RS		3.9
gMVP		0.50
Mutation Taster		=67/33	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: rs764212214; hg19: chr12-2791727;