rs59954346

Positions:

• chr16-1209337-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_021098.3(CACNA1H):​c.3669C>T​(p.Ala1223Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,597,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.747

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]

CACNA1H (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-1209337-C-T is Benign according to our data. Variant chr16-1209337-C-T is described in ClinVar as [Benign]. Clinvar id is 460094.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-1209337-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.747 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00109 (166/152324) while in subpopulation NFE AF= 0.00193 (131/68020). AF 95% confidence interval is 0.00166. There are 0 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 166 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3669C>T	p.Ala1223Ala	synonymous_variant	17/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3669C>T	p.Ala1223Ala	synonymous_variant	17/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.3669C>T	p.Ala1223Ala	synonymous_variant	16/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.3630C>T	p.Ala1210Ala	synonymous_variant	17/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.3669C>T		non_coding_transcript_exon_variant	17/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1582C>T		non_coding_transcript_exon_variant	17/35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*1582C>T		3_prime_UTR_variant	17/35	5		ENSP00000491488.1
CACNA1H	ENST00000637236.2	n.-19C>T		upstream_gene_variant		5		ENSP00000492650.2

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000955 AC: 219 AN: 229278 Hom.: 1 AF XY: 0.00103 AC XY: 131 AN XY: 127054

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000264

Gnomad FIN exome AF: 0.000852

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.00141 AC: 2035 AN: 1445638 Hom.: 2 Cov.: 32 AF XY: 0.00140 AC XY: 1006 AN XY: 719604

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000761

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.000946

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74482

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00102

EpiCase AF: 0.00196

EpiControl AF: 0.00208

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.0
DANN	Benign	0.83

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: rs59954346; hg19: chr16-1259337;