NM_000719.7:c.171C>T

Variant names:

• chr12-2115345-C-T
• rs34419050
• NM_000719.7:c.171C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.171C>T​(p.Asp57Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,588,598 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 34)
  • Exomes 𝑓: 0.024 (496 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.301
• Publications: 8 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-2115345-C-T is Benign according to our data. Variant chr12-2115345-C-T is described in ClinVar as Benign. ClinVar VariationId is 35767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.301 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0164 (2505/152362) while in subpopulation SAS AF = 0.0379 (183/4832). AF 95% confidence interval is 0.0334. There are 28 homozygotes in GnomAd4. There are 1210 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2505 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.171C>T	p.Asp57Asp	synonymous	Exon 2 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.171C>T	p.Asp57Asp	synonymous	Exon 2 of 47	NP_001161095.1
	CACNA1C	NM_199460.4		c.171C>T	p.Asp57Asp	synonymous	Exon 2 of 50	NP_955630.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.171C>T	p.Asp57Asp	synonymous	Exon 2 of 47	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.171C>T	p.Asp57Asp	synonymous	Exon 2 of 47	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.261C>T	p.Asp87Asp	synonymous	Exon 2 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2506 AN: 152244 Hom.: 28 Cov.: 34

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0380

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0205 AC: 4122 AN: 201186 AF XY: 0.0224

Gnomad AFR exome AF: 0.00325

Gnomad AMR exome AF: 0.00892

Gnomad ASJ exome AF: 0.0193

Gnomad EAS exome AF: 0.000139

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0236 AC: 33845 AN: 1436236 Hom.: 496 Cov.: 32 AF XY: 0.0244 AC XY: 17395 AN XY: 713112

African (AFR) AF: 0.00320 AC: 105 AN: 32844

American (AMR) AF: 0.00909 AC: 370 AN: 40692

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 488 AN: 25704

East Asian (EAS) AF: 0.000132 AC: 5 AN: 37934

South Asian (SAS) AF: 0.0390 AC: 3245 AN: 83270

European-Finnish (FIN) AF: 0.0114 AC: 539 AN: 47400

Middle Eastern (MID) AF: 0.0301 AC: 173 AN: 5742

European-Non Finnish (NFE) AF: 0.0252 AC: 27754 AN: 1103080

Other (OTH) AF: 0.0196 AC: 1166 AN: 59570

GnomAD4 genome AF: 0.0164 AC: 2505 AN: 152362 Hom.: 28 Cov.: 34 AF XY: 0.0162 AC XY: 1210 AN XY: 74514

African (AFR) AF: 0.00418 AC: 174 AN: 41594

American (AMR) AF: 0.0114 AC: 174 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0379 AC: 183 AN: 4832

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10630

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0256 AC: 1740 AN: 68026

Other (OTH) AF: 0.0151 AC: 32 AN: 2116

Alfa AF: 0.0210 Hom.: 5

Bravo AF: 0.0149

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	5.6
DANN	Benign	0.78
PhyloP100		-0.30
PromoterAI		-0.077	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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: rs34419050; hg19: chr12-2224511;