12-2664897-C-T

Variant names:

• chr12-2664897-C-T
• rs756717724
• NM_000719.7:c.4305C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.4305C>T​(p.Ser1435Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,518 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 33)
  • Exomes 𝑓: 0.000038 (1 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.25
• 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]

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-2664897-C-T is Benign according to our data. Variant chr12-2664897-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.25 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4539C>T	p.Ser1513Ser	synonymous_variant	Exon 37 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4272C>T	p.Ser1424Ser	synonymous_variant	Exon 34 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4470C>T	p.Ser1490Ser	synonymous_variant	Exon 36 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4449C>T	p.Ser1483Ser	synonymous_variant	Exon 37 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4371C>T	p.Ser1457Ser	synonymous_variant	Exon 35 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4395C>T	p.Ser1465Ser	synonymous_variant	Exon 35 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4395C>T	p.Ser1465Ser	synonymous_variant	Exon 35 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4395C>T	p.Ser1465Ser	synonymous_variant	Exon 35 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4395C>T	p.Ser1465Ser	synonymous_variant	Exon 35 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4389C>T	p.Ser1463Ser	synonymous_variant	Exon 36 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4380C>T	p.Ser1460Ser	synonymous_variant	Exon 36 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4365C>T	p.Ser1455Ser	synonymous_variant	Exon 36 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4356C>T	p.Ser1452Ser	synonymous_variant	Exon 35 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4347C>T	p.Ser1449Ser	synonymous_variant	Exon 35 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4272C>T	p.Ser1424Ser	synonymous_variant	Exon 34 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4272C>T	p.Ser1424Ser	synonymous_variant	Exon 34 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4266C>T	p.Ser1422Ser	synonymous_variant	Exon 34 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4305C>T	p.Ser1435Ser	synonymous_variant	Exon 35 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4296C>T	p.Ser1432Ser	synonymous_variant	Exon 35 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4272C>T	p.Ser1424Ser	synonymous_variant	Exon 34 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000483 AC: 12 AN: 248602 AF XY: 0.0000519

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: 0.0000711

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461318 Hom.: 1 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 726914

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111688

Other (OTH) AF: 0.0000497 AC: 3 AN: 60366

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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: 2094

Alfa AF: 0.0000731 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 09, 2015

GeneDx

Significance: 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. -

Long QT syndrome Benign:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 16, 2020

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	-0.77
CADD	Benign	0.13
DANN	Benign	0.81
PhyloP100		-6.2

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: rs756717724; hg19: chr12-2774063;