rs2753326

Positions:

• chr16-1211219-A-G

Variant summary

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

The NM_021098.3(CACNA1H):​c.4275A>G​(p.Ser1425Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,612,062 control chromosomes in the GnomAD database, including 304,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33496 hom., cov: 35)
  • Exomes 𝑓: 0.61 (271373 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.37

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=-0.81).
• BP6: Variant 16-1211219-A-G is Benign according to our data. Variant chr16-1211219-A-G is described in ClinVar as [Benign]. Clinvar id is 585642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1211219-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4275A>G	p.Ser1425Ser	synonymous_variant	22/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4275A>G	p.Ser1425Ser	synonymous_variant	22/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4275A>G	p.Ser1425Ser	synonymous_variant	21/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4236A>G	p.Ser1412Ser	synonymous_variant	22/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.498A>G	p.Ser166Ser	synonymous_variant	5/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.498A>G	p.Ser166Ser	synonymous_variant	5/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.498A>G	p.Ser166Ser	synonymous_variant	5/17	1		ENSP00000454581.2
CACNA1H	ENST00000637236.2	n.*245A>G		non_coding_transcript_exon_variant	6/6	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4275A>G		non_coding_transcript_exon_variant	22/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2188A>G		non_coding_transcript_exon_variant	22/35	5		ENSP00000491488.1
CACNA1H	ENST00000637236.2	n.*245A>G		3_prime_UTR_variant	6/6	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1	n.*2188A>G		3_prime_UTR_variant	22/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99901 AN: 151880 Hom.: 33467 Cov.: 35

Gnomad AFR AF: 0.732

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.660

GnomAD3 exomes AF: 0.652 AC: 161970 AN: 248412 Hom.: 53985 AF XY: 0.641 AC XY: 86547 AN XY: 135060

Gnomad AFR exome AF: 0.735

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.892

Gnomad SAS exome AF: 0.566

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.588

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.605 AC: 883872 AN: 1460064 Hom.: 271373 Cov.: 54 AF XY: 0.603 AC XY: 438091 AN XY: 726346

Gnomad4 AFR exome AF: 0.743

Gnomad4 AMR exome AF: 0.732

Gnomad4 ASJ exome AF: 0.692

Gnomad4 EAS exome AF: 0.902

Gnomad4 SAS exome AF: 0.571

Gnomad4 FIN exome AF: 0.690

Gnomad4 NFE exome AF: 0.581

Gnomad4 OTH exome AF: 0.628

GnomAD4 genome AF: 0.658 AC: 99975 AN: 151998 Hom.: 33496 Cov.: 35 AF XY: 0.665 AC XY: 49429 AN XY: 74302

Gnomad4 AFR AF: 0.732

Gnomad4 AMR AF: 0.700

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.878

Gnomad4 SAS AF: 0.569

Gnomad4 FIN AF: 0.710

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.665

Alfa AF: 0.613 Hom.: 12385

Bravo AF: 0.667

Asia WGS AF: 0.730 AC: 2539 AN: 3478

EpiCase AF: 0.599

EpiControl AF: 0.587

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	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	- -

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	-0.81
CADD	Benign	0.052
DANN	Benign	0.46

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: rs2753326; hg19: chr16-1261219; COSMIC: COSV61998699; COSMIC: COSV61998699;