rs200289321

Variant names:

• chr12-2486244-A-C
• rs200289321
• NM_000719.7:c.898A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-2486244-A-C
• chr12-2486244-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.898A>C​(p.Asn300His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N300D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.562
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24850023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.988A>C	p.Asn330His	missense_variant	Exon 6 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.988A>C	p.Asn330His	missense_variant	Exon 6 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.988A>C	p.Asn330His	missense_variant	Exon 6 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.988A>C	p.Asn330His	missense_variant	Exon 6 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.988A>C	p.Asn330His	missense_variant	Exon 6 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.988A>C	p.Asn330His	missense_variant	Exon 6 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.898A>C	p.Asn300His	missense_variant	Exon 6 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.847A>C	p.Asn283His	missense_variant	Exon 5 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.898A>C		non_coding_transcript_exon_variant	Exon 6 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461272 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726910

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

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111624

Other (OTH) AF: 0.00 AC: 0 AN: 60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
CardioboostArm	Benign	0.000026
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Benign	0.84
DEOGEN2	Benign	0.34	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.96	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PhyloP100		0.56
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.47	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.56	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0070, 0.0, 0.91, 0.0040	.;B;.;B;B;B;B;B;B;B;B;B;B;B;P;B;.;B;B;.;.;.;B
Vest4		0.26
MutPred		0.51		Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);Gain of catalytic residue at Q301 (P = 0.0021);
MVP		0.79
MPC		1.1
ClinPred		0.28	T
GERP RS		5.0
gMVP		0.91
Mutation Taster		=49/51	disease causing

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: rs200289321; hg19: chr12-2595410;