16-1218001-C-G

Variant names:

• chr16-1218001-C-G
• rs537055062
• NM_021098.3:c.5406C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021098.3(CACNA1H):​c.5406C>G​(p.Phe1802Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,068 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.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5406C>G	p.Phe1802Leu	missense_variant	Exon 32 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5406C>G	p.Phe1802Leu	missense_variant	Exon 32 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5388C>G	p.Phe1796Leu	missense_variant	Exon 30 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5367C>G	p.Phe1789Leu	missense_variant	Exon 32 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1644C>G	p.Phe548Leu	missense_variant	Exon 14 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1629C>G	p.Phe543Leu	missense_variant	Exon 15 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1611C>G	p.Phe537Leu	missense_variant	Exon 14 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*487C>G		non_coding_transcript_exon_variant	Exon 32 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3257C>G		non_coding_transcript_exon_variant	Exon 32 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*487C>G		3_prime_UTR_variant	Exon 32 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3257C>G		3_prime_UTR_variant	Exon 32 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000876 AC: 2 AN: 228436 Hom.: 0 AF XY: 0.00000803 AC XY: 1 AN XY: 124500

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000598

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450068 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720364

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000230

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D;D;D;.
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.9	D;.;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;.;D;D
Polyphen		0.99	D;.;D;D
Vest4		0.85
MutPred		0.89		Gain of helix (P = 0.0425);.;.;.;
MVP		0.98
ClinPred		0.99	D
GERP RS		1.6
Varity_R		0.84
gMVP		0.95

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: rs537055062; hg19: chr16-1268001; COSMIC: COSV105861623; COSMIC: COSV105861623;