rs374177870

Positions:

• chr12-2679727-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.5375A>G​(p.Glu1792Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,606,640 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 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 8.55

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 -6 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=0.23178971).
• BP6: Variant 12-2679727-A-G is Benign according to our data. Variant chr12-2679727-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526952.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5375A>G	p.Glu1792Gly	missense_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5375A>G	p.Glu1792Gly	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.5375A>G	p.Glu1792Gly	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5375A>G	p.Glu1792Gly	missense_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5609A>G	p.Glu1870Gly	missense_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5375A>G	p.Glu1792Gly	missense_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5342A>G	p.Glu1781Gly	missense_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5540A>G	p.Glu1847Gly	missense_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5519A>G	p.Glu1840Gly	missense_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5498A>G	p.Glu1833Gly	missense_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5375A>G	p.Glu1792Gly	missense_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5375A>G	p.Glu1792Gly	missense_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5465A>G	p.Glu1822Gly	missense_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5465A>G	p.Glu1822Gly	missense_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5465A>G	p.Glu1822Gly	missense_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5465A>G	p.Glu1822Gly	missense_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5459A>G	p.Glu1820Gly	missense_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5450A>G	p.Glu1817Gly	missense_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5435A>G	p.Glu1812Gly	missense_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5432A>G	p.Glu1811Gly	missense_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5432A>G	p.Glu1811Gly	missense_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5432A>G	p.Glu1811Gly	missense_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5426A>G	p.Glu1809Gly	missense_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5417A>G	p.Glu1806Gly	missense_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5399A>G	p.Glu1800Gly	missense_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5399A>G	p.Glu1800Gly	missense_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5393A>G	p.Glu1798Gly	missense_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5375A>G	p.Glu1792Gly	missense_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5375A>G	p.Glu1792Gly	missense_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5375A>G	p.Glu1792Gly	missense_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5375A>G	p.Glu1792Gly	missense_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5375A>G	p.Glu1792Gly	missense_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5366A>G	p.Glu1789Gly	missense_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5342A>G	p.Glu1781Gly	missense_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000863 AC: 2 AN: 231748 Hom.: 0 AF XY: 0.00000793 AC XY: 1 AN XY: 126078

Gnomad AFR exome AF: 0.0000748

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000970

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000309 AC: 45 AN: 1454486 Hom.: 0 Cov.: 34 AF XY: 0.0000374 AC XY: 27 AN XY: 722858

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000307

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74328

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000247 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 16, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2022

The p.E1792G variant (also known as c.5375A>G), located in coding exon 42 of the CACNA1C gene, results from an A to G substitution at nucleotide position 5375. The glutamic acid at codon 1792 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 01, 2024

Variant summary: CACNA1C c.5375A>G (p.Glu1792Gly) results in a non-conservative amino acid change in 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 3.8e-05 in 1606640 control chromosomes. The observed variant frequency is approximately 3.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05). c.5375A>G has been reported in the literature in at least one individual with arrhythmia, however these report(s) do not provide unequivocal conclusions about association of the variant with Timothy Syndrome (e.g., Richard_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30471092). ClinVar contains an entry for this variant (Variation ID: 526952). Based on the evidence outlined above, the variant was classified as likely benign. -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0046	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.23	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	0.098	D
MutationAssessor	Benign	1.9	.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.80	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.34
Sift	Benign	0.068	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D;.
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		0.49, 0.082, 0.0030, 0.0010, 0.80, 0.60, 0.14, 0.76, 0.45, 0.34, 0.55, 0.73, 0.0090	.;P;B;B;B;P;P;P;B;P;P;P;B;P;P;.;P;B;.;.;.;P;.
Vest4		0.49
MVP		0.52
MPC		0.22
ClinPred		0.42	T
GERP RS		4.9
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs374177870; hg19: chr12-2788893;