rs369356684

Variant names:

• chr16-1205127-C-A
• rs369356684
• NM_021098.3:c.2465C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1205127-C-A
• chr16-1205127-C-G
• chr16-1205127-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021098.3(CACNA1H):​c.2465C>A​(p.Thr822Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T822S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.92
• Publications: 1 publications found

Genes affected

CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

CACNA1H Gene-Disease associations (from GenCC):

• hyperaldosteronism, familial, type IV

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, childhood absence, susceptibility to, 6

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.2426C>A	p.Thr809Asn	missense_variant	Exon 11 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.2426C>A	p.Thr809Asn	missense_variant	Exon 11 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.2465C>A	p.Thr822Asn	missense_variant	Exon 11 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*378C>A		non_coding_transcript_exon_variant	Exon 11 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*1912C>A		non_coding_transcript_exon_variant	Exon 10 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.2465C>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1	n.*378C>A		3_prime_UTR_variant	Exon 11 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*1912C>A		3_prime_UTR_variant	Exon 10 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247334 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459932 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726278

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111690

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.36
LIST_S2	Pathogenic	0.99	D;D;D;.
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M;.;M;M
PhyloP100		5.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.6	D;.;D;D
Sift	Uncertain	0.0020	D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D
Vest4		0.73
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.82
gMVP		0.89
Mutation Taster		=26/74	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: rs369356684; hg19: chr16-1255127;