rs551355331

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-2680395-C-A
• chr12-2680395-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001167625.2(CACNA1C):​c.5444C>A​(p.Thr1815Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,559,234 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: CACNA1C NM_001167625.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04078877).
• BP6: Variant 12-2680395-C-A is Benign according to our data. Variant chr12-2680395-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191426.
• BS2: High AC in GnomAd4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167625.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.5444+599C>A		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5444+599C>A		intron	N/A	NP_001161095.1
	CACNA1C	NM_001167625.2		c.5444C>A	p.Thr1815Asn	missense	Exon 42 of 47	NP_001161097.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000406454.8	TSL:5	c.5477C>A	p.Thr1826Asn	missense	Exon 43 of 48	ENSP00000385896.3
	CACNA1C	ENST00000399634.6	TSL:5	c.5444C>A	p.Thr1815Asn	missense	Exon 42 of 47	ENSP00000382542.2
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5444+599C>A		intron	N/A	ENSP00000382512.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000175 AC: 29 AN: 165460 AF XY: 0.000204

Gnomad AFR exome AF: 0.000108

Gnomad AMR exome AF: 0.000230

Gnomad ASJ exome AF: 0.000116

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000307

Gnomad OTH exome AF: 0.000217

GnomAD4 exome AF: 0.000196 AC: 276 AN: 1406954 Hom.: 0 Cov.: 31 AF XY: 0.000210 AC XY: 146 AN XY: 694776

African (AFR) AF: 0.0000311 AC: 1 AN: 32180

American (AMR) AF: 0.000270 AC: 10 AN: 37036

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 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: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.000227 AC: 246 AN: 1082932

Other (OTH) AF: 0.000291 AC: 17 AN: 58362

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74466

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000112 AC: 13

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.2
DANN	Benign	0.62
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.022	N
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.37	T
PhyloP100		-0.062
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.18
Sift	Benign	0.35	T
Sift4G	Benign	0.49	T
Polyphen		0.0010	B
Vest4		0.085
MVP		0.50
ClinPred		0.0036	T
GERP RS		-0.59
Mutation Taster		=97/3	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;