chr12-2680395-C-T

Variant names:

• chr12-2680395-C-T
• rs551355331
• ENST00000406454.8:c.5477C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000406454.8(CACNA1C):​c.5477C>T​(p.Thr1826Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,406,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/17 in silico tools predict 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. T1826N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CACNA1C ENST00000406454.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620
• Publications: 2 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05910638).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000406454.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.5444+599C>T		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5444+599C>T		intron	N/A	NP_001161095.1
	CACNA1C	NM_001167625.2		c.5444C>T	p.Thr1815Ile	missense	Exon 42 of 47	NP_001161097.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000406454.8	TSL:5	c.5477C>T	p.Thr1826Ile	missense	Exon 43 of 48	ENSP00000385896.3
	CACNA1C	ENST00000399634.6	TSL:5	c.5444C>T	p.Thr1815Ile	missense	Exon 42 of 47	ENSP00000382542.2
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5444+599C>T		intron	N/A	ENSP00000382512.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1406956 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 694778

African (AFR) AF: 0.00 AC: 0 AN: 32180

American (AMR) AF: 0.00 AC: 0 AN: 37036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25226

East Asian (EAS) AF: 0.00 AC: 0 AN: 36680

South Asian (SAS) AF: 0.00 AC: 0 AN: 79764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1082934

Other (OTH) AF: 0.00 AC: 0 AN: 58362

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.0
DANN	Benign	0.45
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.018	N
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.36	T
PhyloP100		-0.062
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.18
Sift	Benign	0.64	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.087
MutPred		0.29		Loss of glycosylation at T1826 (P = 0.0159)
MVP		0.34
ClinPred		0.018	T
GERP RS		-0.59
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs551355331; hg19: chr12-2789561;