rs1051978823

Positions:

• chr12-2679794-C-A
• chr12-2679794-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_000719.7(CACNA1C):​c.5442C>A​(p.Asn1814Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense, splice_region
• Scores: Splicing: ADA: 0.00004558
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.23

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.07097262).
• BP6: Variant 12-2679794-C-A is Benign according to our data. Variant chr12-2679794-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3232242.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_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.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5676C>A	p.Asn1892Lys	missense_variant, splice_region_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5409C>A	p.Asn1803Lys	missense_variant, splice_region_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5607C>A	p.Asn1869Lys	missense_variant, splice_region_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5586C>A	p.Asn1862Lys	missense_variant, splice_region_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5565C>A	p.Asn1855Lys	missense_variant, splice_region_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5532C>A	p.Asn1844Lys	missense_variant, splice_region_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5532C>A	p.Asn1844Lys	missense_variant, splice_region_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5532C>A	p.Asn1844Lys	missense_variant, splice_region_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5532C>A	p.Asn1844Lys	missense_variant, splice_region_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5526C>A	p.Asn1842Lys	missense_variant, splice_region_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5517C>A	p.Asn1839Lys	missense_variant, splice_region_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5502C>A	p.Asn1834Lys	missense_variant, splice_region_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5499C>A	p.Asn1833Lys	missense_variant, splice_region_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5499C>A	p.Asn1833Lys	missense_variant, splice_region_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5499C>A	p.Asn1833Lys	missense_variant, splice_region_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5493C>A	p.Asn1831Lys	missense_variant, splice_region_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5484C>A	p.Asn1828Lys	missense_variant, splice_region_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5466C>A	p.Asn1822Lys	missense_variant, splice_region_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5466C>A	p.Asn1822Lys	missense_variant, splice_region_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5460C>A	p.Asn1820Lys	missense_variant, splice_region_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5442C>A	p.Asn1814Lys	missense_variant, splice_region_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5433C>A	p.Asn1811Lys	missense_variant, splice_region_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5409C>A	p.Asn1803Lys	missense_variant, splice_region_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1403900 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 692524

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2023

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	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.2
DANN	Benign	0.69
DEOGEN2	Benign	0.0018	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.42	N
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.064	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	-0.47	T
MutationAssessor	Benign	-2.1	.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.53	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.25
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		0.089
MutPred		0.38		.;.;.;.;.;.;.;.;.;.;Gain of ubiquitination at N1862 (P = 0.0085);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.38
MPC		0.22
ClinPred		0.050	T
GERP RS		0.65
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.038
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: rs1051978823; hg19: chr12-2788960;