chr12-2682039-G-C

Position:

• chr12-2682039-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Moderate BS2

The NM_199460.4(CACNA1C):​c.5678G>C​(p.Arg1893Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,446,912 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.068177104).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5445-511G>C		intron_variant		ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5445-511G>C		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>C	p.Arg1923Thr	missense_variant	45/50			ENSP00000507184.1
CACNA1C	ENST00000327702.12	c.5534G>C	p.Arg1845Thr	missense_variant	43/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5534G>C	p.Arg1845Thr	missense_variant	43/48	5		ENSP00000382526.1
CACNA1C	ENST00000399603.6	c.5445-511G>C		intron_variant		5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5445-511G>C		intron_variant		1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454.8	c.5658-511G>C		intron_variant		5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5625-511G>C		intron_variant		5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5610-511G>C		intron_variant				ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5589-511G>C		intron_variant		1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5568-511G>C		intron_variant		1		ENSP00000341092.3
CACNA1C	ENST00000682462.1	c.5535-511G>C		intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5535-511G>C		intron_variant				ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5535-511G>C		intron_variant				ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5535-511G>C		intron_variant				ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5529-511G>C		intron_variant		1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5520-511G>C		intron_variant		5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5505-511G>C		intron_variant		1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5502-511G>C		intron_variant		1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5502-511G>C		intron_variant		1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5502-511G>C		intron_variant		1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5496-511G>C		intron_variant		1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5487-511G>C		intron_variant				ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5469-511G>C		intron_variant		1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5469-511G>C		intron_variant		1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5463-511G>C		intron_variant		1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5445-511G>C		intron_variant		1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5445-511G>C		intron_variant		1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5445-511G>C		intron_variant		1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5445-511G>C		intron_variant		1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5445-511G>C		intron_variant				ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5436-511G>C		intron_variant				ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5412-511G>C		intron_variant				ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446912 Hom.: 0 Cov.: 27 AF XY: 0.00000277 AC XY: 2 AN XY: 720776

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000455

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	8.7
DEOGEN2	Benign	0.023	T;T
MetaRNN	Benign	0.068	T;T
Sift4G	Benign	0.51	T;T
Vest4		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10774054; hg19: chr12-2791205;