NM_000719.7:c.4656C>T

Variant names:

• chr12-2668965-C-T
• rs372600490
• NM_000719.7:c.4656C>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.4656C>T​(p.Ser1552Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,898 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.281
• 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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 12-2668965-C-T is Benign according to our data. Variant chr12-2668965-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1535961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.281 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4890C>T	p.Ser1630Ser	synonymous_variant	Exon 40 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4623C>T	p.Ser1541Ser	synonymous_variant	Exon 37 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4821C>T	p.Ser1607Ser	synonymous_variant	Exon 39 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4800C>T	p.Ser1600Ser	synonymous_variant	Exon 40 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4722C>T	p.Ser1574Ser	synonymous_variant	Exon 38 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4746C>T	p.Ser1582Ser	synonymous_variant	Exon 38 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4746C>T	p.Ser1582Ser	synonymous_variant	Exon 38 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4746C>T	p.Ser1582Ser	synonymous_variant	Exon 38 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4746C>T	p.Ser1582Ser	synonymous_variant	Exon 38 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4740C>T	p.Ser1580Ser	synonymous_variant	Exon 39 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4731C>T	p.Ser1577Ser	synonymous_variant	Exon 39 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4716C>T	p.Ser1572Ser	synonymous_variant	Exon 39 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4707C>T	p.Ser1569Ser	synonymous_variant	Exon 38 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4698C>T	p.Ser1566Ser	synonymous_variant	Exon 38 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4623C>T	p.Ser1541Ser	synonymous_variant	Exon 37 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4623C>T	p.Ser1541Ser	synonymous_variant	Exon 37 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4617C>T	p.Ser1539Ser	synonymous_variant	Exon 37 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4656C>T	p.Ser1552Ser	synonymous_variant	Exon 38 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4647C>T	p.Ser1549Ser	synonymous_variant	Exon 38 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4623C>T	p.Ser1541Ser	synonymous_variant	Exon 37 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250646 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461728 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727174

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111872

Other (OTH) AF: 0.0000497 AC: 3 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

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

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 21, 2024

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	-0.28
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		-0.28
Mutation Taster		=89/11	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: rs372600490; hg19: chr12-2778131; COSMIC: COSV100217216;