rs10774054

Positions:

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

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 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. 4/4 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.225 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.04096961).
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5445-511G>A		intron_variant		ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5445-511G>A		intron_variant		ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000682544.1	c.5768G>A	p.Arg1923Lys	missense_variant	45/50			ENSP00000507184.1
CACNA1C	ENST00000327702.12	c.5534G>A	p.Arg1845Lys	missense_variant	43/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5534G>A	p.Arg1845Lys	missense_variant	43/48	5		ENSP00000382526.1
CACNA1C	ENST00000399603.6	c.5445-511G>A		intron_variant		5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5445-511G>A		intron_variant		1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454.8	c.5658-511G>A		intron_variant		5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5625-511G>A		intron_variant		5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5610-511G>A		intron_variant				ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5589-511G>A		intron_variant		1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5568-511G>A		intron_variant		1		ENSP00000341092.3
CACNA1C	ENST00000682462.1	c.5535-511G>A		intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5535-511G>A		intron_variant				ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5535-511G>A		intron_variant				ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5535-511G>A		intron_variant				ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5529-511G>A		intron_variant		1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5520-511G>A		intron_variant		5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5505-511G>A		intron_variant		1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5502-511G>A		intron_variant		1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5502-511G>A		intron_variant		1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5502-511G>A		intron_variant		1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5496-511G>A		intron_variant		1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5487-511G>A		intron_variant				ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5469-511G>A		intron_variant		1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5469-511G>A		intron_variant		1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5463-511G>A		intron_variant		1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5445-511G>A		intron_variant		1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5445-511G>A		intron_variant		1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5445-511G>A		intron_variant		1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5445-511G>A		intron_variant		1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5445-511G>A		intron_variant				ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5436-511G>A		intron_variant				ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5412-511G>A		intron_variant				ENSP00000507309.1

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

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00145

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: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10774054; hg19: chr12-2791205;