12-2686214-G-A

Position:

• chr12-2686214-G-A

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.5729G>A​(p.Arg1910Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,613,760 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.86

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=0.01367119).
• BP6: Variant 12-2686214-G-A is Benign according to our data. Variant chr12-2686214-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456983.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000112 (17/152326) while in subpopulation EAS AF= 0.00212 (11/5184). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5729G>A	p.Arg1910Gln	missense_variant	45/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5729G>A	p.Arg1910Gln	missense_variant	45/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5729G>A	p.Arg1910Gln	missense_variant	45/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5729G>A	p.Arg1910Gln	missense_variant	45/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6068G>A	p.Arg2023Gln	missense_variant	48/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5942G>A	p.Arg1981Gln	missense_variant	46/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5909G>A	p.Arg1970Gln	missense_variant	45/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5894G>A	p.Arg1965Gln	missense_variant	46/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5873G>A	p.Arg1958Gln	missense_variant	47/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5852G>A	p.Arg1951Gln	missense_variant	45/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5834G>A	p.Arg1945Gln	missense_variant	46/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5834G>A	p.Arg1945Gln	missense_variant	46/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5819G>A	p.Arg1940Gln	missense_variant	45/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5819G>A	p.Arg1940Gln	missense_variant	45/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5819G>A	p.Arg1940Gln	missense_variant	45/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5819G>A	p.Arg1940Gln	missense_variant	45/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5813G>A	p.Arg1938Gln	missense_variant	46/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5804G>A	p.Arg1935Gln	missense_variant	46/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5789G>A	p.Arg1930Gln	missense_variant	46/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5786G>A	p.Arg1929Gln	missense_variant	45/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5786G>A	p.Arg1929Gln	missense_variant	45/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5786G>A	p.Arg1929Gln	missense_variant	45/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5780G>A	p.Arg1927Gln	missense_variant	45/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5771G>A	p.Arg1924Gln	missense_variant	45/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5753G>A	p.Arg1918Gln	missense_variant	44/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5753G>A	p.Arg1918Gln	missense_variant	44/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5747G>A	p.Arg1916Gln	missense_variant	44/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5729G>A	p.Arg1910Gln	missense_variant	45/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5729G>A	p.Arg1910Gln	missense_variant	45/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5729G>A	p.Arg1910Gln	missense_variant	45/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5729G>A	p.Arg1910Gln	missense_variant	45/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5729G>A	p.Arg1910Gln	missense_variant	45/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5720G>A	p.Arg1907Gln	missense_variant	45/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5696G>A	p.Arg1899Gln	missense_variant	44/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

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: 0.0000963 AC: 24 AN: 249306 Hom.: 0 AF XY: 0.0000887 AC XY: 12 AN XY: 135252

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000890

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000200 AC: 292 AN: 1461434 Hom.: 1 Cov.: 32 AF XY: 0.000191 AC XY: 139 AN XY: 727006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00441

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74482

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000888 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000827 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CACNA1C-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2022

The CACNA1C c.5729G>A variant is predicted to result in the amino acid substitution p.Arg1910Gln. This variant was reported in a study of ion channel-related genes in individuals with autism spectrum disorder (Supplementary Table 1, Lee et al 2021. PubMed ID: 34712263). This variant is reported in 0.097% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-2795380-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2020

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	Benign	-0.56	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Benign	0.63
DEOGEN2	Benign	0.0027	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.7	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.064
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.20
MVP		0.19
MPC		0.22
ClinPred		0.0040	T
GERP RS		-0.28
gMVP		0.22

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: rs190288386; hg19: chr12-2795380; COSMIC: COSV59699370; COSMIC: COSV59699370;