16-1220649-C-T

Position:

• chr16-1220649-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):​c.6717C>T​(p.Gly2239=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,603,900 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (9 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.206

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=-0.72).
• BP6: Variant 16-1220649-C-T is Benign according to our data. Variant chr16-1220649-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1220649-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.206 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00203 (308/152048) while in subpopulation AFR AF= 0.0027 (112/41494). AF 95% confidence interval is 0.00229. There are 0 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 308 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6717C>T	p.Gly2239=	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.6717C>T	p.Gly2239=	synonymous_variant	35/35	1	NM_021098.3	ENSP00000334198	P4

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 151930 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00233

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00120 AC: 268 AN: 223490 Hom.: 0 AF XY: 0.00122 AC XY: 151 AN XY: 123648

Gnomad AFR exome AF: 0.00254

Gnomad AMR exome AF: 0.000306

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000135

Gnomad FIN exome AF: 0.000248

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.000539

GnomAD4 exome AF: 0.00172 AC: 2495 AN: 1451852 Hom.: 9 Cov.: 35 AF XY: 0.00168 AC XY: 1215 AN XY: 721612

Gnomad4 AFR exome AF: 0.00232

Gnomad4 AMR exome AF: 0.000300

Gnomad4 ASJ exome AF: 0.000930

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00201

Gnomad4 OTH exome AF: 0.00175

GnomAD4 genome AF: 0.00203 AC: 308 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74320

Gnomad4 AFR AF: 0.00270

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00233

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.00204

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	CACNA1H: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.4
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143733790; hg19: chr16-1270649; COSMIC: COSV52352492; COSMIC: COSV52352492;