rs41276710

Variant names:

• chr12-2665667-T-C
• rs41276710
• NM_000719.7:c.4485T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000719.7(CACNA1C):​c.4485T>C​(p.Asp1495Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00979 in 1,613,432 control chromosomes in the GnomAD database, including 701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (350 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (351 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.470
• Publications: 4 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]

CACNA1C Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-2665667-T-C is Benign according to our data. Variant chr12-2665667-T-C is described in ClinVar as Benign. ClinVar VariationId is 93407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

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.4485T>C	p.Asp1495Asp	synonymous	Exon 36 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.4485T>C	p.Asp1495Asp	synonymous	Exon 36 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.4629T>C	p.Asp1543Asp	synonymous	Exon 38 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.4485T>C	p.Asp1495Asp	synonymous	Exon 36 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.4485T>C	p.Asp1495Asp	synonymous	Exon 36 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.4719T>C	p.Asp1573Asp	synonymous	Exon 38 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5938 AN: 152092 Hom.: 348 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0122 AC: 3039 AN: 249384 AF XY: 0.0102

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.00858

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.000442

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.00595

GnomAD4 exome AF: 0.00673 AC: 9839 AN: 1461222 Hom.: 351 Cov.: 31 AF XY: 0.00652 AC XY: 4739 AN XY: 726914

African (AFR) AF: 0.141 AC: 4730 AN: 33466

American (AMR) AF: 0.00897 AC: 401 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26122

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39690

South Asian (SAS) AF: 0.00820 AC: 707 AN: 86246

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53376

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5762

European-Non Finnish (NFE) AF: 0.00284 AC: 3162 AN: 1111504

Other (OTH) AF: 0.0116 AC: 698 AN: 60346

GnomAD4 genome AF: 0.0391 AC: 5953 AN: 152210 Hom.: 350 Cov.: 32 AF XY: 0.0378 AC XY: 2813 AN XY: 74432

African (AFR) AF: 0.129 AC: 5364 AN: 41514

American (AMR) AF: 0.0148 AC: 227 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5168

South Asian (SAS) AF: 0.00996 AC: 48 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00348 AC: 237 AN: 68008

Other (OTH) AF: 0.0289 AC: 61 AN: 2110

Alfa AF: 0.0181 Hom.: 123

Bravo AF: 0.0445

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00445

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.2
DANN	Benign	0.84
PhyloP100		0.47
Mutation Taster		=93/7	polymorphism (auto)

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: rs41276710; hg19: chr12-2774833;