rs10774054

Variant names:

• chr12-2682039-G-A
• rs10774054
• ENST00000682544.1:c.5768G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2682039-G-A
• chr12-2682039-G-C
• chr12-2682039-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_199460.4(CACNA1C):​c.5678G>A​(p.Arg1893Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000065 in 1,599,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: CACNA1C NM_199460.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.331
• Publications: 25 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04096961).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000401 (61/152192) while in subpopulation AFR AF = 0.00145 (60/41434). AF 95% confidence interval is 0.00115. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 61 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199460.4. 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.5445-511G>A		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5445-511G>A		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.5678G>A	p.Arg1893Lys	missense	Exon 45 of 50	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000682544.1		c.5768G>A	p.Arg1923Lys	missense	Exon 45 of 50	ENSP00000507184.1	A0A804HIR0
	CACNA1C	ENST00000327702.12	TSL:1	c.5534G>A	p.Arg1845Lys	missense	Exon 43 of 48	ENSP00000329877.7	A0A0A0MR67
	CACNA1C	ENST00000399617.6	TSL:5	c.5534G>A	p.Arg1845Lys	missense	Exon 43 of 48	ENSP00000382526.1	A0A0A0MSA1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.0000297 AC: 43 AN: 1446912 Hom.: 0 Cov.: 27 AF XY: 0.0000277 AC XY: 20 AN XY: 720776

African (AFR) AF: 0.00127 AC: 42 AN: 33178

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098634

Other (OTH) AF: 0.00 AC: 0 AN: 59860

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74348

African (AFR) AF: 0.00145 AC: 60 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.88
CADD	Benign	10
DEOGEN2	Benign	0.013	T
MetaRNN	Benign	0.041	T
PhyloP100		0.33
Sift4G	Benign	0.86	T
Vest4		0.11

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10774054; hg19: chr12-2791205;