rs36117280

Positions:

• chr16-1200389-A-G
• chr16-1200389-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000348261.11(CACNA1H):​c.937A>G​(p.Met313Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,605,316 control chromosomes in the GnomAD database, including 18,100 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1408 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16692 hom.)
• Consequence: CACNA1H ENST00000348261.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.365

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=0.0017673373).
• BP6: Variant 16-1200389-A-G is Benign according to our data. Variant chr16-1200389-A-G is described in ClinVar as [Benign]. Clinvar id is 585657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1200389-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.937A>G	p.Met313Val	missense_variant	7/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.937A>G	p.Met313Val	missense_variant	7/35	1	NM_021098.3	ENSP00000334198	P4

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19440 AN: 152186 Hom.: 1404 Cov.: 32

Gnomad AFR AF: 0.0847

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0649

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.133 AC: 31097 AN: 233864 Hom.: 2234 AF XY: 0.140 AC XY: 17934 AN XY: 128240

Gnomad AFR exome AF: 0.0782

Gnomad AMR exome AF: 0.0667

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.0664

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.149 AC: 216241 AN: 1453012 Hom.: 16692 Cov.: 34 AF XY: 0.150 AC XY: 108507 AN XY: 722448

Gnomad4 AFR exome AF: 0.0787

Gnomad4 AMR exome AF: 0.0716

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.0434

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.128 AC: 19462 AN: 152304 Hom.: 1408 Cov.: 32 AF XY: 0.129 AC XY: 9610 AN XY: 74464

Gnomad4 AFR AF: 0.0852

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.0644

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.172

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.137

Alfa AF: 0.139 Hom.: 1094

Bravo AF: 0.120

TwinsUK AF: 0.149 AC: 553

ALSPAC AF: 0.154 AC: 593

ESP6500AA AF: 0.0705 AC: 286

ESP6500EA AF: 0.144 AC: 1201

ExAC AF: 0.133 AC: 15899

Asia WGS AF: 0.121 AC: 422 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	2.1
DANN	Benign	0.48
DEOGEN2	Benign	0.35	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.0082	T;T;T;.
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.60	N;.;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.33	N;.;N;N
REVEL	Benign	0.27
Sift	Benign	0.67	T;.;T;T
Sift4G	Benign	1.0	T;.;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.18
ClinPred		0.00026	T
GERP RS		1.3
Varity_R		0.040
gMVP		0.76

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: rs36117280; hg19: chr16-1250389; COSMIC: COSV61993451; COSMIC: COSV61993451;