rs750289082

Positions:

• chr12-2682582-C-G
• chr12-2682582-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.5477C>G​(p.Ala1826Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 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)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23

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 Uncertain_significance. Variant got 1 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 7.2674 (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=0.14432088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5477C>G	p.Ala1826Gly	missense_variant	43/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5477C>G	p.Ala1826Gly	missense_variant	43/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5477C>G	p.Ala1826Gly	missense_variant	43/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5477C>G	p.Ala1826Gly	missense_variant	43/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5816C>G	p.Ala1939Gly	missense_variant	46/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5690C>G	p.Ala1897Gly	missense_variant	44/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5657C>G	p.Ala1886Gly	missense_variant	43/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5642C>G	p.Ala1881Gly	missense_variant	44/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5621C>G	p.Ala1874Gly	missense_variant	45/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5600C>G	p.Ala1867Gly	missense_variant	43/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5582C>G	p.Ala1861Gly	missense_variant	44/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5582C>G	p.Ala1861Gly	missense_variant	44/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5567C>G	p.Ala1856Gly	missense_variant	43/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5567C>G	p.Ala1856Gly	missense_variant	43/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5567C>G	p.Ala1856Gly	missense_variant	43/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5567C>G	p.Ala1856Gly	missense_variant	43/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5561C>G	p.Ala1854Gly	missense_variant	44/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5552C>G	p.Ala1851Gly	missense_variant	44/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5537C>G	p.Ala1846Gly	missense_variant	44/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5534C>G	p.Ala1845Gly	missense_variant	43/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5534C>G	p.Ala1845Gly	missense_variant	43/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5534C>G	p.Ala1845Gly	missense_variant	43/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5528C>G	p.Ala1843Gly	missense_variant	43/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5519C>G	p.Ala1840Gly	missense_variant	43/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5501C>G	p.Ala1834Gly	missense_variant	42/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5501C>G	p.Ala1834Gly	missense_variant	42/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5495C>G	p.Ala1832Gly	missense_variant	42/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5477C>G	p.Ala1826Gly	missense_variant	43/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5477C>G	p.Ala1826Gly	missense_variant	43/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5477C>G	p.Ala1826Gly	missense_variant	43/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5477C>G	p.Ala1826Gly	missense_variant	43/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5477C>G	p.Ala1826Gly	missense_variant	43/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5468C>G	p.Ala1823Gly	missense_variant	43/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5444C>G	p.Ala1815Gly	missense_variant	42/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.54
DEOGEN2	Benign	0.010	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.74	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.14	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	-0.17	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.89	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.29
Sift	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.091, 0.0, 0.043, 0.010, 0.14, 0.011, 0.079, 0.22, 0.055, 0.084	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.10
MVP		0.48
MPC		0.19
ClinPred		0.066	T
GERP RS		0.93
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-2791748;