12-2566522-A-T

Variant names:

• chr12-2566522-A-T
• rs1467561684
• NM_000719.7:c.1609A>T

Variant summary

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

The NM_000719.7(CACNA1C):​c.1609A>T​(p.Asn537Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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 5 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, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1699A>T	p.Asn567Tyr	missense_variant	Exon 12 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1774A>T	p.Asn592Tyr	missense_variant	Exon 13 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1699A>T	p.Asn567Tyr	missense_variant	Exon 12 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1699A>T	p.Asn567Tyr	missense_variant	Exon 12 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1699A>T	p.Asn567Tyr	missense_variant	Exon 12 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1699A>T	p.Asn567Tyr	missense_variant	Exon 12 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1684A>T	p.Asn562Tyr	missense_variant	Exon 13 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1684A>T	p.Asn562Tyr	missense_variant	Exon 13 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1600A>T	p.Asn534Tyr	missense_variant	Exon 12 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*216A>T		non_coding_transcript_exon_variant	Exon 10 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*216A>T		3_prime_UTR_variant	Exon 10 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152106 Hom.: 0 Cov.: 33 FAILED QC

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000208 AC: 3 AN: 1442292 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000473

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: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74306

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.93	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	Pathogenic	4.2	.;H;.;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;H;H;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.1	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	0.87
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.93
MutPred		0.50		.;Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);
MVP		0.97
MPC		2.5
ClinPred		1.0	D
GERP RS		2.8
gMVP		1.0

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: rs1467561684; hg19: chr12-2675688;