12-2115327-G-T

Variant names:

• chr12-2115327-G-T
• rs563315606
• NM_000719.7:c.153G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000719.7(CACNA1C):​c.153G>T​(p.Ser51Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,433,018 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S51S) has been classified 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: 0.992
• Publications: 0 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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-2115327-G-T is Benign according to our data. Variant chr12-2115327-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1123225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.992 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.153G>T	p.Ser51Ser	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.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.243G>T	p.Ser81Ser	synonymous_variant	Exon 2 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.243G>T	p.Ser81Ser	synonymous_variant	Exon 2 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.243G>T	p.Ser81Ser	synonymous_variant	Exon 2 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.243G>T	p.Ser81Ser	synonymous_variant	Exon 2 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.243G>T	p.Ser81Ser	synonymous_variant	Exon 2 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.243G>T	p.Ser81Ser	synonymous_variant	Exon 2 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.153G>T	p.Ser51Ser	synonymous_variant	Exon 2 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.102G>T	p.Ser34Ser	synonymous_variant	Exon 1 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.153G>T		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000101 AC: 2 AN: 197292 AF XY: 0.00

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: 0.0000616

Gnomad NFE exome AF: 0.0000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1433018 Hom.: 0 Cov.: 32 AF XY: 0.00000281 AC XY: 2 AN XY: 711288

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

African (AFR) AF: 0.0000307 AC: 1 AN: 32594

American (AMR) AF: 0.00 AC: 0 AN: 40164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.00 AC: 0 AN: 37526

South Asian (SAS) AF: 0.00 AC: 0 AN: 83140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101336

Other (OTH) AF: 0.00 AC: 0 AN: 59398

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.055673), which strongly suggests a high chance of mosaicism in these individuals.

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

Oct 08, 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	-0.41
CADD	Benign	9.4
DANN	Benign	0.73
PhyloP100		0.99
PromoterAI		0.010	Neutral

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: rs563315606; hg19: chr12-2224493;