rs57315342

Variant names:

• chr16-1210783-G-A
• rs57315342
• NM_021098.3:c.4039-4G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.4039-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,599,932 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 35)
  • Exomes 𝑓: 0.0035 (36 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001501
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.75

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-1210783-G-A is Benign according to our data. Variant chr16-1210783-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460106.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr16-1210783-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00293 (446/152358) while in subpopulation SAS AF= 0.00435 (21/4832). AF 95% confidence interval is 0.00312. There are 3 homozygotes in gnomad4. There are 203 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 446 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4039-4G>A		splice_region_variant, intron_variant	Intron 20 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4039-4G>A		splice_region_variant, intron_variant	Intron 20 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4039-4G>A		splice_region_variant, intron_variant	Intron 19 of 32	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4000-4G>A		splice_region_variant, intron_variant	Intron 20 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.262-4G>A		splice_region_variant, intron_variant	Intron 3 of 16	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.262-4G>A		splice_region_variant, intron_variant	Intron 3 of 17	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.262-4G>A		splice_region_variant, intron_variant	Intron 3 of 16	1		ENSP00000454581.2
CACNA1H	ENST00000637236.2	n.*9-4G>A		splice_region_variant, intron_variant	Intron 4 of 5	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4039-4G>A		splice_region_variant, intron_variant	Intron 20 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1952-4G>A		splice_region_variant, intron_variant	Intron 20 of 34	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 446 AN: 152240 Hom.: 3 Cov.: 35

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00359 AC: 849 AN: 236414 Hom.: 16 AF XY: 0.00378 AC XY: 491 AN XY: 129874

Gnomad AFR exome AF: 0.000332

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.00354

Gnomad FIN exome AF: 0.000154

Gnomad NFE exome AF: 0.00316

Gnomad OTH exome AF: 0.00644

GnomAD4 exome AF: 0.00355 AC: 5133 AN: 1447574 Hom.: 36 Cov.: 39 AF XY: 0.00365 AC XY: 2628 AN XY: 720622

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.0327

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00372

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00315

Gnomad4 OTH exome AF: 0.00475

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152358 Hom.: 3 Cov.: 35 AF XY: 0.00272 AC XY: 203 AN XY: 74508

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00348

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00554 Hom.: 2

Bravo AF: 0.00289

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1H: BP4, BS2 -

Oct 06, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 05, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1H-related disorder Benign:1

Apr 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.020
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: rs57315342; hg19: chr16-1260783; COSMIC: COSV61996921; COSMIC: COSV61996921;