rs1555517834

Positions:

• chr16-1212513-A-C
• chr16-1212513-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021098.3(CACNA1H):​c.4762A>C​(p.Thr1588Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,610,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19339335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4762A>C	p.Thr1588Pro	missense_variant, splice_region_variant	26/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4762A>C	p.Thr1588Pro	missense_variant, splice_region_variant	26/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000638323.1	c.4723A>C	p.Thr1575Pro	missense_variant, splice_region_variant	26/35	5		ENSP00000492267.1
CACNA1H	ENST00000564231.5	c.985A>C	p.Thr329Pro	missense_variant, splice_region_variant	9/18	1		ENSP00000457555.2
CACNA1H	ENST00000565831.6	c.4759+375A>C		intron_variant		1		ENSP00000455840.1
CACNA1H	ENST00000569107.5	c.1015+342A>C		intron_variant		1		ENSP00000454990.2
CACNA1H	ENST00000562079.5	c.982+375A>C		intron_variant		1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.4700A>C		splice_region_variant, non_coding_transcript_exon_variant	26/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2613A>C		splice_region_variant, non_coding_transcript_exon_variant	26/35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*2613A>C		3_prime_UTR_variant	26/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151890 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458826 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 725642

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151890 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74192

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.33	T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	0.18	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.81	N;.
REVEL	Uncertain	0.44
Sift	Benign	0.26	T;.
Sift4G	Benign	0.32	T;.
Polyphen		1.0	D;.
Vest4		0.39
MutPred		0.35		Loss of phosphorylation at T1588 (P = 0.002);.;
MVP		0.91
ClinPred		0.49	T
GERP RS		3.4
Varity_R		0.20
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1555517834; hg19: chr16-1262513;