chr12-2691054-A-C

Variant names:

• chr12-2691054-A-C
• NM_000719.7:c.6272A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000719.7(CACNA1C):​c.6272A>C​(p.Asn2091Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,080 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. N2091S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21

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-AS1 (HGNC:):

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.265633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6272A>C	p.Asn2091Thr	missense_variant	Exon 47 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6272A>C	p.Asn2091Thr	missense_variant	Exon 47 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6272A>C	p.Asn2091Thr	missense_variant	Exon 47 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6272A>C	p.Asn2091Thr	missense_variant	Exon 47 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6611A>C	p.Asn2204Thr	missense_variant	Exon 50 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6485A>C	p.Asn2162Thr	missense_variant	Exon 48 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6452A>C	p.Asn2151Thr	missense_variant	Exon 47 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6437A>C	p.Asn2146Thr	missense_variant	Exon 48 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6416A>C	p.Asn2139Thr	missense_variant	Exon 49 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6395A>C	p.Asn2132Thr	missense_variant	Exon 47 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6377A>C	p.Asn2126Thr	missense_variant	Exon 48 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6377A>C	p.Asn2126Thr	missense_variant	Exon 48 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6362A>C	p.Asn2121Thr	missense_variant	Exon 47 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6362A>C	p.Asn2121Thr	missense_variant	Exon 47 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6362A>C	p.Asn2121Thr	missense_variant	Exon 47 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6362A>C	p.Asn2121Thr	missense_variant	Exon 47 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6356A>C	p.Asn2119Thr	missense_variant	Exon 48 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6347A>C	p.Asn2116Thr	missense_variant	Exon 48 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6332A>C	p.Asn2111Thr	missense_variant	Exon 48 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6329A>C	p.Asn2110Thr	missense_variant	Exon 47 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6329A>C	p.Asn2110Thr	missense_variant	Exon 47 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6329A>C	p.Asn2110Thr	missense_variant	Exon 47 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6323A>C	p.Asn2108Thr	missense_variant	Exon 47 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6314A>C	p.Asn2105Thr	missense_variant	Exon 47 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6296A>C	p.Asn2099Thr	missense_variant	Exon 46 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6296A>C	p.Asn2099Thr	missense_variant	Exon 46 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6290A>C	p.Asn2097Thr	missense_variant	Exon 46 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6272A>C	p.Asn2091Thr	missense_variant	Exon 47 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6272A>C	p.Asn2091Thr	missense_variant	Exon 47 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6272A>C	p.Asn2091Thr	missense_variant	Exon 47 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6272A>C	p.Asn2091Thr	missense_variant	Exon 47 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6272A>C	p.Asn2091Thr	missense_variant	Exon 47 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6263A>C	p.Asn2088Thr	missense_variant	Exon 47 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6239A>C	p.Asn2080Thr	missense_variant	Exon 46 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455080 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723254

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Benign	0.17
Sift	Benign	0.097	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.048, 0.91, 0.0010, 1.0, 0.036, 0.99, 1.0, 1.0, 0.041	.;D;B;P;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;B;.
Vest4		0.31
MVP		0.58
MPC		0.54
ClinPred		0.96	D
GERP RS		4.5
gMVP		0.68

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2800220;