12-2685771-C-T

Variant names:

• chr12-2685771-C-T
• rs201777030
• NM_000719.7:c.5609C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000719.7(CACNA1C):​c.5609C>T​(p.Thr1870Met) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1870K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.01
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057109594).
• BP6: Variant 12-2685771-C-T is Benign according to our data. Variant chr12-2685771-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. 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.5609C>T	p.Thr1870Met	missense	Exon 44 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5609C>T	p.Thr1870Met	missense	Exon 44 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.5858C>T	p.Thr1953Met	missense	Exon 47 of 50	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5609C>T	p.Thr1870Met	missense	Exon 44 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5609C>T	p.Thr1870Met	missense	Exon 44 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.5948C>T	p.Thr1983Met	missense	Exon 47 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 145 AN: 141892 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000696

Gnomad ASJ AF: 0.000309

Gnomad EAS AF: 0.00187

Gnomad SAS AF: 0.00153

Gnomad FIN AF: 0.00209

Gnomad MID AF: 0.00360

Gnomad NFE AF: 0.000863

Gnomad OTH AF: 0.000526

GnomAD2 exomes AF: 0.00102 AC: 252 AN: 246240 AF XY: 0.000942

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000676

Gnomad FIN exome AF: 0.00697

Gnomad NFE exome AF: 0.000394

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000658 AC: 946 AN: 1437826 Hom.: 1 Cov.: 31 AF XY: 0.000654 AC XY: 468 AN XY: 715836

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000182 AC: 6 AN: 32974

American (AMR) AF: 0.000384 AC: 17 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.000738 AC: 29 AN: 39316

South Asian (SAS) AF: 0.000902 AC: 77 AN: 85330

European-Finnish (FIN) AF: 0.00517 AC: 269 AN: 52050

Middle Eastern (MID) AF: 0.000363 AC: 2 AN: 5514

European-Non Finnish (NFE) AF: 0.000467 AC: 510 AN: 1093058

Other (OTH) AF: 0.000606 AC: 36 AN: 59436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00102 AC: 145 AN: 142000 Hom.: 1 Cov.: 32 AF XY: 0.00103 AC XY: 71 AN XY: 69258

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00106 AC: 41 AN: 38660

American (AMR) AF: 0.000695 AC: 10 AN: 14390

Ashkenazi Jewish (ASJ) AF: 0.000309 AC: 1 AN: 3236

East Asian (EAS) AF: 0.00188 AC: 9 AN: 4796

South Asian (SAS) AF: 0.00153 AC: 7 AN: 4580

European-Finnish (FIN) AF: 0.00209 AC: 20 AN: 9568

Middle Eastern (MID) AF: 0.00388 AC: 1 AN: 258

European-Non Finnish (NFE) AF: 0.000863 AC: 55 AN: 63732

Other (OTH) AF: 0.000522 AC: 1 AN: 1916

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0938 Hom.: 3188

ExAC AF: 0.00352 AC: 426

EpiCase AF: 0.000439

EpiControl AF: 0.000357

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.73	T
PhyloP100		6.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Benign	0.10	T
Sift4G	Benign	0.23	T
Polyphen		0.99	D
Vest4		0.49
MVP		0.52
MPC		0.33
ClinPred		0.029	T
GERP RS		4.3
gMVP		0.39
Mutation Taster		=79/21	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: rs201777030; hg19: chr12-2794937; COSMIC: COSV59698677; COSMIC: COSV59698677;