rs374807892

Variant names:

• chr16-1218385-C-G
• rs374807892
• NM_021098.3:c.5621C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-1218385-C-G
• chr16-1218385-C-T

Variant summary

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

The NM_021098.3(CACNA1H):​c.5621C>G​(p.Ala1874Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,284 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 0.0000066 (0 hom., cov: 34)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07

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.5621C>G	p.Ala1874Gly	missense_variant	Exon 33 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5621C>G	p.Ala1874Gly	missense_variant	Exon 33 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5603C>G	p.Ala1868Gly	missense_variant	Exon 31 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5582C>G	p.Ala1861Gly	missense_variant	Exon 33 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1859C>G	p.Ala620Gly	missense_variant	Exon 15 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1844C>G	p.Ala615Gly	missense_variant	Exon 16 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1826C>G	p.Ala609Gly	missense_variant	Exon 15 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*702C>G		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3472C>G		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*702C>G		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3472C>G		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 34

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000590 AC: 1 AN: 169590 Hom.: 0 AF XY: 0.0000111 AC XY: 1 AN XY: 90060

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: 0.0000432

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152284 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000881 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;.;.;.
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T;T;T;.
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D;.;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D;.;D;D
Sift4G	Benign	0.071	T;.;T;T
Polyphen		0.14	B;.;D;D
Vest4		0.34
MutPred		0.31		Loss of helix (P = 0.0033);.;.;.;
MVP		0.96
ClinPred		0.91	D
GERP RS		3.1
Varity_R		0.41
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374807892; hg19: chr16-1268385;