16-1213837-C-G

Variant names:

• chr16-1213837-C-G
• rs370292995
• NM_021098.3:c.4835C>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_021098.3(CACNA1H):​c.4835C>G​(p.Ser1612Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,598,320 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: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308

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_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4835C>G	p.Ser1612Trp	missense_variant	Exon 27 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4835C>G	p.Ser1612Trp	missense_variant	Exon 27 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4817C>G	p.Ser1606Trp	missense_variant	Exon 25 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4796C>G	p.Ser1599Trp	missense_variant	Exon 27 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1073C>G	p.Ser358Trp	missense_variant	Exon 9 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1058C>G	p.Ser353Trp	missense_variant	Exon 10 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1040C>G	p.Ser347Trp	missense_variant	Exon 9 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.4773C>G		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2686C>G		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*2686C>G		3_prime_UTR_variant	Exon 27 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000447 AC: 1 AN: 223572 Hom.: 0 AF XY: 0.00000824 AC XY: 1 AN XY: 121300

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: 0.00000994

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1446166 Hom.: 0 Cov.: 31 AF XY: 0.00000836 AC XY: 6 AN XY: 717898

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: 0.0000145

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.16	N
LIST_S2	Pathogenic	0.98	D;D;D;.
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Uncertain	0.46	D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D;.;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0080	D;.;D;D
Sift4G	Uncertain	0.0090	D;.;D;D
Polyphen		0.98	D;.;B;B
Vest4		0.63
MutPred		0.53		Loss of disorder (P = 0.0085);.;.;.;
MVP		0.91
ClinPred		0.76	D
GERP RS		2.8
Varity_R		0.58
gMVP		0.72

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: rs370292995; hg19: chr16-1263837;