rs777945001

Variant names:

• chr12-2567592-G-A
• rs777945001
• NM_000719.7:c.1693G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2567592-G-A
• chr12-2567592-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1 PP2 PP3_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.1693G>A​(p.Ala565Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,596,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 6.76

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a repeat II (size 246) in uniprot entity CAC1C_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000719.7
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• BP6: Variant 12-2567592-G-A is Benign according to our data. Variant chr12-2567592-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190643.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1783G>A	p.Ala595Thr	missense_variant	Exon 13 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1858G>A	p.Ala620Thr	missense_variant	Exon 14 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1783G>A	p.Ala595Thr	missense_variant	Exon 13 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1783G>A	p.Ala595Thr	missense_variant	Exon 13 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1783G>A	p.Ala595Thr	missense_variant	Exon 13 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1783G>A	p.Ala595Thr	missense_variant	Exon 13 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1768G>A	p.Ala590Thr	missense_variant	Exon 14 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1768G>A	p.Ala590Thr	missense_variant	Exon 14 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1684G>A	p.Ala562Thr	missense_variant	Exon 13 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1693G>A	p.Ala565Thr	missense_variant	Exon 13 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*300G>A		non_coding_transcript_exon_variant	Exon 11 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*300G>A		3_prime_UTR_variant	Exon 11 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 7 AN: 220120 Hom.: 0 AF XY: 0.0000589 AC XY: 7 AN XY: 118822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000258

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000187 AC: 27 AN: 1444266 Hom.: 0 Cov.: 31 AF XY: 0.0000293 AC XY: 21 AN XY: 716664

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: 0.000324

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000413 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

May 31, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign in association with a CACNA1C-related disorder to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34436362) -

not specified Benign:1

Nov 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1C c.1693G>A (p.Ala565Thr) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 1596520 control chromosomes. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05). To our knowledge, no occurrence of c.1693G>A in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 190643). Based on the evidence outlined above, the variant was classified as likely benign. -

Long QT syndrome Benign:1

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Apr 09, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Uncertain	0.099	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.88	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	Benign	1.3	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.9	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	0.81
Sift	Benign	0.089	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.16	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, 1.0, 0.88, 0.74, 0.85, 1.0, 0.78, 1.0	.;D;D;P;P;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.81
MutPred		0.59		.;Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);
MVP		0.87
MPC		1.8
ClinPred		0.87	D
GERP RS		5.1
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs777945001; hg19: chr12-2676758;