12-2566562-A-G

Position:

• chr12-2566562-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 3P and 14B. PM1 PP2 BP4_Moderate BP6_Very_Strong BS2

The NM_000719.7(CACNA1C):​c.1649A>G​(p.Asn550Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000388 in 1,598,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.25

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 Benign. Variant got -11 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 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=0.1659621).
• BP6: Variant 12-2566562-A-G is Benign according to our data. Variant chr12-2566562-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 575658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1649A>G	p.Asn550Ser	missense_variant	12/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1649A>G	p.Asn550Ser	missense_variant	12/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1649A>G	p.Asn550Ser	missense_variant	12/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1739A>G	p.Asn580Ser	missense_variant	12/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1649A>G	p.Asn550Ser	missense_variant	12/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1649A>G	p.Asn550Ser	missense_variant	12/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1814A>G	p.Asn605Ser	missense_variant	13/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1649A>G	p.Asn550Ser	missense_variant	12/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1649A>G	p.Asn550Ser	missense_variant	12/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1649A>G	p.Asn550Ser	missense_variant	12/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1739A>G	p.Asn580Ser	missense_variant	12/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1739A>G	p.Asn580Ser	missense_variant	12/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1739A>G	p.Asn580Ser	missense_variant	12/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1739A>G	p.Asn580Ser	missense_variant	12/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1649A>G	p.Asn550Ser	missense_variant	12/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1724A>G	p.Asn575Ser	missense_variant	13/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1649A>G	p.Asn550Ser	missense_variant	12/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1724A>G	p.Asn575Ser	missense_variant	13/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1649A>G	p.Asn550Ser	missense_variant	12/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1649A>G	p.Asn550Ser	missense_variant	12/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1649A>G	p.Asn550Ser	missense_variant	12/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1649A>G	p.Asn550Ser	missense_variant	12/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1640A>G	p.Asn547Ser	missense_variant	12/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1649A>G	p.Asn550Ser	missense_variant	12/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*256A>G		non_coding_transcript_exon_variant	10/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*256A>G		3_prime_UTR_variant	10/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000178 AC: 4 AN: 224750 Hom.: 0 AF XY: 0.0000165 AC XY: 2 AN XY: 121332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000618

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000610

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000990

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000408 AC: 59 AN: 1446438 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 29 AN XY: 717842

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000232

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: 0.0000498

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74348

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000740 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2022

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	-0.18	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.37	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.011
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.17	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	-0.17	T
MutationAssessor	Benign	0.43	.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.88	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.48	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	0.53	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, 0.0010, 0.018	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B
Vest4		0.14
MutPred		0.35		.;Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);
MVP		0.70
MPC		0.85
ClinPred		0.13	T
GERP RS		4.8
gMVP		0.42

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: rs781306162; hg19: chr12-2675728;