12-2685819-G-T

Variant names:

• chr12-2685819-G-T
• rs748198629
• NM_000719.7:c.5657G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000719.7(CACNA1C):​c.5657G>T​(p.Gly1886Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1886A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.50
• Publications: 5 publications found

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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24558082).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5657G>T	p.Gly1886Val	missense_variant	Exon 44 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5657G>T	p.Gly1886Val	missense_variant	Exon 44 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5657G>T	p.Gly1886Val	missense_variant	Exon 44 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5657G>T	p.Gly1886Val	missense_variant	Exon 44 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5996G>T	p.Gly1999Val	missense_variant	Exon 47 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5870G>T	p.Gly1957Val	missense_variant	Exon 45 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5837G>T	p.Gly1946Val	missense_variant	Exon 44 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5822G>T	p.Gly1941Val	missense_variant	Exon 45 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5801G>T	p.Gly1934Val	missense_variant	Exon 46 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5780G>T	p.Gly1927Val	missense_variant	Exon 44 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5762G>T	p.Gly1921Val	missense_variant	Exon 45 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5762G>T	p.Gly1921Val	missense_variant	Exon 45 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5747G>T	p.Gly1916Val	missense_variant	Exon 44 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5747G>T	p.Gly1916Val	missense_variant	Exon 44 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5747G>T	p.Gly1916Val	missense_variant	Exon 44 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5747G>T	p.Gly1916Val	missense_variant	Exon 44 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5741G>T	p.Gly1914Val	missense_variant	Exon 45 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5732G>T	p.Gly1911Val	missense_variant	Exon 45 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5717G>T	p.Gly1906Val	missense_variant	Exon 45 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5714G>T	p.Gly1905Val	missense_variant	Exon 44 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5714G>T	p.Gly1905Val	missense_variant	Exon 44 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5714G>T	p.Gly1905Val	missense_variant	Exon 44 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5708G>T	p.Gly1903Val	missense_variant	Exon 44 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5699G>T	p.Gly1900Val	missense_variant	Exon 44 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5681G>T	p.Gly1894Val	missense_variant	Exon 43 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5681G>T	p.Gly1894Val	missense_variant	Exon 43 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5675G>T	p.Gly1892Val	missense_variant	Exon 43 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5657G>T	p.Gly1886Val	missense_variant	Exon 44 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5657G>T	p.Gly1886Val	missense_variant	Exon 44 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5657G>T	p.Gly1886Val	missense_variant	Exon 44 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5657G>T	p.Gly1886Val	missense_variant	Exon 44 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5657G>T	p.Gly1886Val	missense_variant	Exon 44 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5648G>T	p.Gly1883Val	missense_variant	Exon 44 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5624G>T	p.Gly1875Val	missense_variant	Exon 43 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460972 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726818

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111222

Other (OTH) AF: 0.0000663 AC: 4 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 08, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
CardioboostArm	Benign	0.0000046
BayesDel_addAF	Benign	0.0085	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.80
DEOGEN2	Benign	0.0097	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.25	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	-0.84	T
PhyloP100		5.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.23
Sift	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.54	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, 0.69, 0.13	.;B;B;B;B;B;B;B;B;B;B;B;B;P;B;.;B;B;.;.;.;B;.
Vest4		0.58
MVP		0.64
MPC		0.26
ClinPred		0.74	D
GERP RS		4.3
gMVP		0.37
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs748198629; hg19: chr12-2794985;