rs367895193

Positions:

• chr12-2634330-G-A
• chr12-2634330-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BP6 BS2

The NM_000719.7(CACNA1C):​c.3862G>A​(p.Ala1288Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 1,581,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 9.81

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 -5 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 7.2674 (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=0.2833093).
• BP6: Variant 12-2634330-G-A is Benign according to our data. Variant chr12-2634330-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190664.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3862G>A	p.Ala1288Thr	missense_variant	30/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3912+618G>A		intron_variant		ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399655.6	c.3862G>A	p.Ala1288Thr	missense_variant	30/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4096G>A	p.Ala1366Thr	missense_variant	32/50			ENSP00000507184.1
CACNA1C	ENST00000399634.6	c.3862G>A	p.Ala1288Thr	missense_variant	30/47	5		ENSP00000382542.2
CACNA1C	ENST00000347598.9	c.4006G>A	p.Ala1336Thr	missense_variant	32/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3862G>A	p.Ala1288Thr	missense_variant	30/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3862G>A	p.Ala1288Thr	missense_variant	30/48	1		ENSP00000329877.7
CACNA1C	ENST00000683781.1	c.3952G>A	p.Ala1318Thr	missense_variant	30/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3952G>A	p.Ala1318Thr	missense_variant	30/47			ENSP00000507612.1
CACNA1C	ENST00000399638.5	c.3946G>A	p.Ala1316Thr	missense_variant	31/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3937G>A	p.Ala1313Thr	missense_variant	31/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3922G>A	p.Ala1308Thr	missense_variant	31/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3862G>A	p.Ala1288Thr	missense_variant	30/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3862G>A	p.Ala1288Thr	missense_variant	30/47	1		ENSP00000382546.1
CACNA1C	ENST00000399629.5	c.3946G>A	p.Ala1316Thr	missense_variant	31/47	1		ENSP00000382537.1
CACNA1C	ENST00000399591.5	c.3862G>A	p.Ala1288Thr	missense_variant	30/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3862G>A	p.Ala1288Thr	missense_variant	30/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3862G>A	p.Ala1288Thr	missense_variant	30/46	1		ENSP00000382557.1
CACNA1C	ENST00000399601.5	c.3862G>A	p.Ala1288Thr	missense_variant	30/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3862G>A	p.Ala1288Thr	missense_variant	30/47	1		ENSP00000382549.1
CACNA1C	ENST00000682686.1	c.3862G>A	p.Ala1288Thr	missense_variant	30/46			ENSP00000507309.1
CACNA1C	ENST00000399603.6	c.3912+618G>A		intron_variant		5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000406454.8	c.3912+618G>A		intron_variant		5		ENSP00000385896.3
CACNA1C	ENST00000683824.1	c.4077+618G>A		intron_variant				ENSP00000507867.1
CACNA1C	ENST00000399617.6	c.3912+618G>A		intron_variant		5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4002+618G>A		intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683956.1	c.4002+618G>A		intron_variant				ENSP00000506882.1
CACNA1C	ENST00000402845.7	c.3912+618G>A		intron_variant		1		ENSP00000385724.3
CACNA1C	ENST00000682336.1	c.3987+618G>A		intron_variant				ENSP00000507898.1
CACNA1C	ENST00000399597.5	c.3912+618G>A		intron_variant		1		ENSP00000382506.1
CACNA1C	ENST00000399644.5	c.3912+618G>A		intron_variant		1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3912+618G>A		intron_variant				ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3903+618G>A		intron_variant				ENSP00000507169.1

Frequencies

GnomAD3 genomes AF: 0.0000265 AC: 4 AN: 150724 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000817 AC: 17 AN: 207986 Hom.: 0 AF XY: 0.0000539 AC XY: 6 AN XY: 111214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00161

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000223

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000482 AC: 69 AN: 1430602 Hom.: 0 Cov.: 29 AF XY: 0.0000466 AC XY: 33 AN XY: 708658

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000183

Gnomad4 OTH exome AF: 0.0000506

GnomAD4 genome AF: 0.0000265 AC: 4 AN: 150724 Hom.: 0 Cov.: 29 AF XY: 0.0000272 AC XY: 2 AN XY: 73486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000664 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2023

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.3	.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.057	T;D;D;T;D;T;D;D;T;T;T;D;T;T;T;T
Sift4G	Benign	0.095	T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;T
Polyphen		0.77, 0.56, 1.0, 0.65, 0.32, 0.51	.;P;P;D;P;P;B;P;D;P;P;P;D;.;P;.
Vest4		0.74
MutPred		0.39		.;.;.;.;.;.;.;.;Gain of catalytic residue at V1339 (P = 0.0032);.;.;.;.;.;.;.;
MVP		0.88
MPC		1.0
ClinPred		0.25	T
GERP RS		5.5
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs367895193; hg19: chr12-2743496;