rs372453886

chr16-1220303-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):c.6371C>T(p.Pro2124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,564,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2124P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.30

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055206597).
• BP6: Variant 16-1220303-C-T is Benign according to our data. Variant chr16-1220303-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 529642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000788 (12/152284) while in subpopulation SAS AF= 0.00186 (9/4828). AF 95% confidence interval is 0.000972. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.6371C>T	p.Pro2124Leu	missense_variant	35/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6371C>T	p.Pro2124Leu	missense_variant	35/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152168 Hom.: 0 Cov.: 35

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: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000270 AC: 51 AN: 188816 Hom.: 0 AF XY: 0.000299 AC XY: 32 AN XY: 107182

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000726

Gnomad SAS exome AF: 0.00126

Gnomad FIN exome AF: 0.0000824

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.000127 AC: 179 AN: 1411916 Hom.: 1 Cov.: 72 AF XY: 0.000164 AC XY: 115 AN XY: 700544

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000258

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00131

Gnomad4 FIN exome AF: 0.0000485

Gnomad4 NFE exome AF: 0.0000521

Gnomad4 OTH exome AF: 0.000189

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152284 Hom.: 0 Cov.: 35 AF XY: 0.000134 AC XY: 10 AN XY: 74452

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000719 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000144 AC: 1

ExAC AF: 0.000236 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.60	T;T;T;.
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.0	N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N;.;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.062	T;.;T;T
Sift4G	Benign	0.71	T;.;T;T
Polyphen		1.0	D;.;P;P
Vest4		0.15
MVP		0.83
ClinPred		0.090	T
GERP RS		3.0
Varity_R		0.024
gMVP		0.11

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: rs372453886; hg19: chr16-1270303;