rs745571869

Positions:

• chr16-1198761-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_021098.3(CACNA1H):​c.790A>G​(p.Ser264Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.39

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29217649).
• BP6: Variant 16-1198761-A-G is Benign according to our data. Variant chr16-1198761-A-G is described in ClinVar as [Benign]. Clinvar id is 460187.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.790A>G	p.Ser264Gly	missense_variant	6/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.790A>G	p.Ser264Gly	missense_variant	6/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.790A>G	p.Ser264Gly	missense_variant	5/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.751A>G	p.Ser251Gly	missense_variant	6/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.790A>G		non_coding_transcript_exon_variant	6/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.790A>G		non_coding_transcript_exon_variant	6/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245520 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

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: 0.00000206 AC: 3 AN: 1459396 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726008

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.;.
Eigen	Benign	-0.0023
Eigen_PC	Benign	-0.0070
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.66	T;T;T;.
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	0.32	N;.;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;.;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.028	D;.;D;D
Sift4G	Benign	0.075	T;.;T;T
Polyphen		0.96	D;.;B;B
Vest4		0.55
MutPred		0.53		Loss of catalytic residue at S264 (P = 0.1216);.;Loss of catalytic residue at S264 (P = 0.1216);Loss of catalytic residue at S264 (P = 0.1216);
MVP		0.89
ClinPred		0.24	T
GERP RS		3.6
Varity_R		0.17
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs745571869; hg19: chr16-1248761;