12-2691170-G-T

Position:

• chr12-2691170-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4 BS2

The NM_000719.7(CACNA1C):​c.6388G>T​(p.Asp2130Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,445,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2130N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.75

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-AS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 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=0.3542294).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6388G>T	p.Asp2130Tyr	missense_variant	47/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6388G>T	p.Asp2130Tyr	missense_variant	47/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6388G>T	p.Asp2130Tyr	missense_variant	47/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6388G>T	p.Asp2130Tyr	missense_variant	47/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6727G>T	p.Asp2243Tyr	missense_variant	50/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6601G>T	p.Asp2201Tyr	missense_variant	48/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6568G>T	p.Asp2190Tyr	missense_variant	47/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6553G>T	p.Asp2185Tyr	missense_variant	48/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6532G>T	p.Asp2178Tyr	missense_variant	49/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6511G>T	p.Asp2171Tyr	missense_variant	47/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6493G>T	p.Asp2165Tyr	missense_variant	48/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6493G>T	p.Asp2165Tyr	missense_variant	48/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6478G>T	p.Asp2160Tyr	missense_variant	47/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6478G>T	p.Asp2160Tyr	missense_variant	47/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6478G>T	p.Asp2160Tyr	missense_variant	47/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6478G>T	p.Asp2160Tyr	missense_variant	47/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6472G>T	p.Asp2158Tyr	missense_variant	48/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6463G>T	p.Asp2155Tyr	missense_variant	48/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6448G>T	p.Asp2150Tyr	missense_variant	48/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6445G>T	p.Asp2149Tyr	missense_variant	47/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6445G>T	p.Asp2149Tyr	missense_variant	47/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6445G>T	p.Asp2149Tyr	missense_variant	47/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6439G>T	p.Asp2147Tyr	missense_variant	47/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6430G>T	p.Asp2144Tyr	missense_variant	47/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6412G>T	p.Asp2138Tyr	missense_variant	46/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6412G>T	p.Asp2138Tyr	missense_variant	46/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6406G>T	p.Asp2136Tyr	missense_variant	46/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6388G>T	p.Asp2130Tyr	missense_variant	47/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6388G>T	p.Asp2130Tyr	missense_variant	47/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6388G>T	p.Asp2130Tyr	missense_variant	47/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6388G>T	p.Asp2130Tyr	missense_variant	47/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6388G>T	p.Asp2130Tyr	missense_variant	47/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6379G>T	p.Asp2127Tyr	missense_variant	47/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6355G>T	p.Asp2119Tyr	missense_variant	46/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1445944 Hom.: 0 Cov.: 30 AF XY: 0.00000419 AC XY: 3 AN XY: 716670

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: 0.00000454

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.35	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	-0.59	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.31
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;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.96, 1.0, 1.0, 0.079, 0.99	.;D;D;D;D;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4		0.48
MVP		0.56
MPC		0.72
ClinPred		1.0	D
GERP RS		4.6
gMVP		0.90

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: rs199473392; hg19: chr12-2800336;