rs60734921

Positions:

• chr16-1202303-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BS1 BS2

The NM_021098.3(CACNA1H):​c.1853C>T​(p.Pro618Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 1,585,064 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P618P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00097 (2 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: 3.46

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34770316).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000479 (73/152304) while in subpopulation NFE AF= 0.000809 (55/68006). AF 95% confidence interval is 0.000638. There are 1 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.1853C>T	p.Pro618Leu	missense_variant	9/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1853C>T	p.Pro618Leu	missense_variant	9/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152186 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000536 AC: 105 AN: 196016 Hom.: 0 AF XY: 0.000493 AC XY: 53 AN XY: 107556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000334

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000790

Gnomad FIN exome AF: 0.000183

Gnomad NFE exome AF: 0.000992

Gnomad OTH exome AF: 0.000974

GnomAD4 exome AF: 0.000966 AC: 1384 AN: 1432760 Hom.: 2 Cov.: 57 AF XY: 0.000970 AC XY: 689 AN XY: 710164

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000979

Gnomad4 FIN exome AF: 0.000164

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.000741

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152304 Hom.: 1 Cov.: 34 AF XY: 0.000497 AC XY: 37 AN XY: 74472

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000870 Hom.: 0

Bravo AF: 0.000521

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000265 AC: 1

ESP6500EA AF: 0.000498 AC: 4

ExAC AF: 0.000530 AC: 62

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2015	The P618L variant in the CACNA1H gene has been reported previously in association with familial cases of epilepsy; however, this variant did not segregate with the disease in all families reported (Heron et al., 2004; Heron et al., 2007). The P618L variant was not observed with any significant frequency in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P618L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional characterization of P618L indicates that this variant results in accelerated channel activation as well as channel inactivation, thereby allowing for greater channel availability of P618L compared to wild type (Khosravani et al., 2005). We interpret P618L as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2018	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

- -

Epilepsy, idiopathic generalized, susceptibility to, 6 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D;D;D;.
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.5	M;.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.6	D;.;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.020	D;.;D;D
Sift4G	Benign	0.18	T;.;T;T
Polyphen		0.89	P;.;D;D
Vest4		0.58
MVP		0.95
ClinPred		0.52	D
GERP RS		4.1
Varity_R		0.29
gMVP		0.63

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: rs60734921; hg19: chr16-1252303;