rs760390307

Variant names:

• chr12-2593247-C-T
• rs760390307
• NM_000719.7:c.2565C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.2565C>T​(p.Val855Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.546
• Publications: 1 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, ClinGen
• 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: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 12-2593247-C-T is Benign according to our data. Variant chr12-2593247-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 527114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.546 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2655C>T	p.Val885Val	synonymous_variant	Exon 19 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2730C>T	p.Val910Val	synonymous_variant	Exon 20 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2655C>T	p.Val885Val	synonymous_variant	Exon 19 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2655C>T	p.Val885Val	synonymous_variant	Exon 19 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2655C>T	p.Val885Val	synonymous_variant	Exon 19 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2655C>T	p.Val885Val	synonymous_variant	Exon 19 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2640C>T	p.Val880Val	synonymous_variant	Exon 20 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2640C>T	p.Val880Val	synonymous_variant	Exon 20 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2556C>T	p.Val852Val	synonymous_variant	Exon 19 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2565C>T	p.Val855Val	synonymous_variant	Exon 19 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1172C>T		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1172C>T		3_prime_UTR_variant	Exon 17 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248448 AF XY: 0.0000371

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461320 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 726870

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111716

Other (OTH) AF: 0.0000331 AC: 2 AN: 60364

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000595

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 17, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: BP4, BP7 -

Long QT syndrome Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 15, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		-0.55

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: rs760390307; hg19: chr12-2702413; COSMIC: COSV59696965;