rs61543423

Variant names:

• chr16-1209076-C-T
• rs61543423
• NM_021098.3:c.3408C>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.3408C>T​(p.Gly1136Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,543,550 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.476

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=-0.74).
• BP6: Variant 16-1209076-C-T is Benign according to our data. Variant chr16-1209076-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 529690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.476 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000236 (36/152276) while in subpopulation NFE AF= 0.000397 (27/68008). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3408C>T	p.Gly1136Gly	synonymous_variant	Exon 17 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3408C>T	p.Gly1136Gly	synonymous_variant	Exon 17 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.3408C>T	p.Gly1136Gly	synonymous_variant	Exon 16 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.3369C>T	p.Gly1123Gly	synonymous_variant	Exon 17 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.3408C>T		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1321C>T		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*1321C>T		3_prime_UTR_variant	Exon 17 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000229 AC: 34 AN: 148452 Hom.: 0 AF XY: 0.000266 AC XY: 22 AN XY: 82736

Gnomad AFR exome AF: 0.000265

Gnomad AMR exome AF: 0.000229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000757

Gnomad NFE exome AF: 0.000412

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000226 AC: 314 AN: 1391274 Hom.: 1 Cov.: 31 AF XY: 0.000220 AC XY: 151 AN XY: 686824

Gnomad4 AFR exome AF: 0.000161

Gnomad4 AMR exome AF: 0.000150

Gnomad4 ASJ exome AF: 0.0000415

Gnomad4 EAS exome AF: 0.0000273

Gnomad4 SAS exome AF: 0.0000778

Gnomad4 FIN exome AF: 0.0000222

Gnomad4 NFE exome AF: 0.000250

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74448

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000200

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely 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	-0.74
CADD	Benign	0.48
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61543423; hg19: chr16-1259076;