16-1207788-G-T

Position:

• chr16-1207788-G-T

Variant summary

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

The NM_021098.3(CACNA1H):​c.3082G>T​(p.Asp1028Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,278 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.38

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3082G>T	p.Asp1028Tyr	missense_variant	15/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3082G>T	p.Asp1028Tyr	missense_variant	15/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.3082G>T	p.Asp1028Tyr	missense_variant	14/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.3043G>T	p.Asp1015Tyr	missense_variant	15/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.3082G>T		non_coding_transcript_exon_variant	15/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*995G>T		non_coding_transcript_exon_variant	15/35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*995G>T		3_prime_UTR_variant	15/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448278 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 719220

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Benign	0.82
DEOGEN2	Benign	0.23	T;.;.;.
Eigen	Benign	0.066
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.66	T;T;T;.
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.2	L;.;L;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.4	D;.;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.35	T;.;T;T
Sift4G	Benign	0.73	T;.;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.68
MutPred		0.26		Gain of phosphorylation at D1028 (P = 0.0302);.;Gain of phosphorylation at D1028 (P = 0.0302);Gain of phosphorylation at D1028 (P = 0.0302);
MVP		0.98
ClinPred		0.80	D
GERP RS		3.6
Varity_R		0.29
gMVP		0.55

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: rs745354512; hg19: chr16-1257788;