16-1201996-C-T

Variant names:

• chr16-1201996-C-T
• rs1057519554
• NM_021098.3:c.1546C>T

Variant summary

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

The NM_021098.3(CACNA1H):​c.1546C>T​(p.His516Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,387,310 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H516Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1546C>T	p.His516Tyr	missense_variant	Exon 9 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1546C>T	p.His516Tyr	missense_variant	Exon 9 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.1546C>T	p.His516Tyr	missense_variant	Exon 8 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.1507C>T	p.His503Tyr	missense_variant	Exon 9 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.1546C>T		non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.1385+161C>T		intron_variant	Intron 9 of 34	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000738 AC: 1 AN: 135550 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73736

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000201

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000288 AC: 4 AN: 1387310 Hom.: 0 Cov.: 36 AF XY: 0.00000293 AC XY: 2 AN XY: 683600

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: 0.00000372

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Focal epilepsy Uncertain:1

Nov 16, 2016

Neurogenetics Laboratory - MEYER, AOU Meyer

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D;D;D;.
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.8	L;.;L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;.;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.019	D;.;D;D
Sift4G	Benign	0.14	T;.;T;T
Polyphen		0.81	P;.;D;D
Vest4		0.46
MutPred		0.36		Gain of phosphorylation at H516 (P = 0.0632);.;Gain of phosphorylation at H516 (P = 0.0632);Gain of phosphorylation at H516 (P = 0.0632);
MVP		0.91
ClinPred		0.85	D
GERP RS		3.9
Varity_R		0.39
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519554; hg19: chr16-1251996;