chr16-1220349-T-C

Position:

• chr16-1220349-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000348261.11(CACNA1H):​c.6417T>C​(p.Asp2139=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.827 in 1,530,922 control chromosomes in the GnomAD database, including 525,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56213 hom., cov: 36)
  • Exomes 𝑓: 0.82 (469035 hom.)
• Consequence: CACNA1H ENST00000348261.11 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.557

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-1220349-T-C is Benign according to our data. Variant chr16-1220349-T-C is described in ClinVar as [Benign]. Clinvar id is 96018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1220349-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.557 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6417T>C	p.Asp2139=	synonymous_variant	35/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6417T>C	p.Asp2139=	synonymous_variant	35/35	1	NM_021098.3	ENSP00000334198	P4

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130447 AN: 152124 Hom.: 56149 Cov.: 36

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.933

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.806

Gnomad OTH AF: 0.862

GnomAD3 exomes AF: 0.858 AC: 141229 AN: 164594 Hom.: 60863 AF XY: 0.856 AC XY: 79535 AN XY: 92862

Gnomad AFR exome AF: 0.903

Gnomad AMR exome AF: 0.870

Gnomad ASJ exome AF: 0.889

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.925

Gnomad FIN exome AF: 0.852

Gnomad NFE exome AF: 0.807

Gnomad OTH exome AF: 0.848

GnomAD4 exome AF: 0.823 AC: 1135149 AN: 1378680 Hom.: 469035 Cov.: 73 AF XY: 0.826 AC XY: 561774 AN XY: 680500

Gnomad4 AFR exome AF: 0.916

Gnomad4 AMR exome AF: 0.865

Gnomad4 ASJ exome AF: 0.896

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.922

Gnomad4 FIN exome AF: 0.855

Gnomad4 NFE exome AF: 0.802

Gnomad4 OTH exome AF: 0.845

GnomAD4 genome AF: 0.858 AC: 130571 AN: 152242 Hom.: 56213 Cov.: 36 AF XY: 0.862 AC XY: 64187 AN XY: 74440

Gnomad4 AFR AF: 0.909

Gnomad4 AMR AF: 0.860

Gnomad4 ASJ AF: 0.903

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.932

Gnomad4 FIN AF: 0.865

Gnomad4 NFE AF: 0.806

Gnomad4 OTH AF: 0.864

Alfa AF: 0.830 Hom.: 14281

Bravo AF: 0.858

Asia WGS AF: 0.962 AC: 3340 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Epilepsy, childhood absence, susceptibility to, 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 03, 2013

- -

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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.22
DANN	Benign	0.44

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: rs4247094; hg19: chr16-1270349; COSMIC: COSV52353255; COSMIC: COSV52353255;