chr12-2607105-G-T

Position:

• chr12-2607105-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000719.7(CACNA1C):​c.3331G>T​(p.Val1111Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60

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-AS3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Dihydropyridine binding (size 89) in uniprot entity CAC1C_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3331G>T	p.Val1111Phe	missense_variant	26/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3331G>T	p.Val1111Phe	missense_variant	26/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3331G>T	p.Val1111Phe	missense_variant	26/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3331G>T	p.Val1111Phe	missense_variant	26/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3481G>T	p.Val1161Phe	missense_variant	27/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3331G>T	p.Val1111Phe	missense_variant	26/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3331G>T	p.Val1111Phe	missense_variant	26/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3496G>T	p.Val1166Phe	missense_variant	27/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3391G>T	p.Val1131Phe	missense_variant	27/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3331G>T	p.Val1111Phe	missense_variant	26/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3331G>T	p.Val1111Phe	missense_variant	26/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3331G>T	p.Val1111Phe	missense_variant	26/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3421G>T	p.Val1141Phe	missense_variant	26/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3421G>T	p.Val1141Phe	missense_variant	26/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3421G>T	p.Val1141Phe	missense_variant	26/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3421G>T	p.Val1141Phe	missense_variant	26/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3331G>T	p.Val1111Phe	missense_variant	26/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3406G>T	p.Val1136Phe	missense_variant	27/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3391G>T	p.Val1131Phe	missense_variant	27/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3331G>T	p.Val1111Phe	missense_variant	26/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3331G>T	p.Val1111Phe	missense_variant	26/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3331G>T	p.Val1111Phe	missense_variant	26/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3331G>T	p.Val1111Phe	missense_variant	26/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3406G>T	p.Val1136Phe	missense_variant	27/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3331G>T	p.Val1111Phe	missense_variant	26/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3331G>T	p.Val1111Phe	missense_variant	26/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3331G>T	p.Val1111Phe	missense_variant	26/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3331G>T	p.Val1111Phe	missense_variant	26/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3331G>T	p.Val1111Phe	missense_variant	26/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3331G>T	p.Val1111Phe	missense_variant	26/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3331G>T	p.Val1111Phe	missense_variant	26/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3331G>T	p.Val1111Phe	missense_variant	26/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3322G>T	p.Val1108Phe	missense_variant	26/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3331G>T	p.Val1111Phe	missense_variant	26/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1938G>T		non_coding_transcript_exon_variant	24/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1938G>T		3_prime_UTR_variant	24/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;.;.;.;.;.;.;.;.;.;.;H;H;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.96
MutPred		0.57		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at S1132 (P = 0);Gain of catalytic residue at S1132 (P = 0);.;.;.;.;.;.;.;.;.;.;
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		4.9
gMVP		1.0

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

LitVar

Other links and lift over

dbSNP: rs766023530; hg19: chr12-2716271;