NM_000719.7:c.234C>T

Variant names:

• chr12-2115408-C-T
• rs1060504924
• NM_000719.7:c.234C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000719.7(CACNA1C):​c.234C>T​(p.Ser78Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,916 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.30

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-2115408-C-T is Benign according to our data. Variant chr12-2115408-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.324C>T	p.Ser108Ser	synonymous_variant	Exon 2 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.324C>T	p.Ser108Ser	synonymous_variant	Exon 2 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.324C>T	p.Ser108Ser	synonymous_variant	Exon 2 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.324C>T	p.Ser108Ser	synonymous_variant	Exon 2 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.324C>T	p.Ser108Ser	synonymous_variant	Exon 2 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.324C>T	p.Ser108Ser	synonymous_variant	Exon 2 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.234C>T	p.Ser78Ser	synonymous_variant	Exon 2 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.183C>T	p.Ser61Ser	synonymous_variant	Exon 1 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.234C>T		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459916 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726308

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

Jan 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 16, 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	-0.45
CADD	Benign	9.3
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060504924; hg19: chr12-2224574;