rs533676935

Positions:

• chr12-2679492-G-A
• chr12-2679492-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.5140G>A​(p.Gly1714Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,606,096 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (1 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.986

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 Benign. Variant got -12 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=0.023467064).
• BP6: Variant 12-2679492-G-A is Benign according to our data. Variant chr12-2679492-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281999.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000475 (69/1453866) while in subpopulation SAS AF= 0.000432 (37/85624). AF 95% confidence interval is 0.000322. There are 1 homozygotes in gnomad4_exome. There are 47 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5140G>A	p.Gly1714Ser	missense_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5140G>A	p.Gly1714Ser	missense_variant	42/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5140G>A	p.Gly1714Ser	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5140G>A	p.Gly1714Ser	missense_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5374G>A	p.Gly1792Ser	missense_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5140G>A	p.Gly1714Ser	missense_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5107G>A	p.Gly1703Ser	missense_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5305G>A	p.Gly1769Ser	missense_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5284G>A	p.Gly1762Ser	missense_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5263G>A	p.Gly1755Ser	missense_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5140G>A	p.Gly1714Ser	missense_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5140G>A	p.Gly1714Ser	missense_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5230G>A	p.Gly1744Ser	missense_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5230G>A	p.Gly1744Ser	missense_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5230G>A	p.Gly1744Ser	missense_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5230G>A	p.Gly1744Ser	missense_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5224G>A	p.Gly1742Ser	missense_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5215G>A	p.Gly1739Ser	missense_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5200G>A	p.Gly1734Ser	missense_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5197G>A	p.Gly1733Ser	missense_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5197G>A	p.Gly1733Ser	missense_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5197G>A	p.Gly1733Ser	missense_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5191G>A	p.Gly1731Ser	missense_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5182G>A	p.Gly1728Ser	missense_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5164G>A	p.Gly1722Ser	missense_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5164G>A	p.Gly1722Ser	missense_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5158G>A	p.Gly1720Ser	missense_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5140G>A	p.Gly1714Ser	missense_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5140G>A	p.Gly1714Ser	missense_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5140G>A	p.Gly1714Ser	missense_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5140G>A	p.Gly1714Ser	missense_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5140G>A	p.Gly1714Ser	missense_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5131G>A	p.Gly1711Ser	missense_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5107G>A	p.Gly1703Ser	missense_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000748 AC: 18 AN: 240618 Hom.: 0 AF XY: 0.0000994 AC XY: 13 AN XY: 130842

Gnomad AFR exome AF: 0.0000699

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000226

Gnomad SAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000475 AC: 69 AN: 1453866 Hom.: 1 Cov.: 31 AF XY: 0.0000651 AC XY: 47 AN XY: 722150

Gnomad4 AFR exome AF: 0.000241

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000432

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74444

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ExAC AF: 0.000116 AC: 14

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2015	- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	1.7
DANN	Benign	0.92
DEOGEN2	Benign	0.0047	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.023	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	-0.23	T
MutationAssessor	Benign	2.0	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.090	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.67	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020, 0.0, 0.0060, 0.0030, 0.0050, 0.011, 0.22	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.17
MutPred		0.33		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at D1761 (P = 0.0057);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.61
MPC		0.19
ClinPred		0.017	T
GERP RS		-4.6
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs533676935; hg19: chr12-2788658;