16-1195518-C-T

Position:

• chr16-1195518-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):​c.498C>T​(p.Tyr166Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,604,376 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (40 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.66

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-1195518-C-T is Benign according to our data. Variant chr16-1195518-C-T is described in ClinVar as [Benign]. Clinvar id is 460135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1195518-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.66 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00479 (729/152234) while in subpopulation EAS AF= 0.0309 (160/5172). AF 95% confidence interval is 0.027. There are 10 homozygotes in gnomad4. There are 508 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 729 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.498C>T	p.Tyr166Tyr	synonymous_variant	4/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.498C>T	p.Tyr166Tyr	synonymous_variant	4/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.498C>T	p.Tyr166Tyr	synonymous_variant	3/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.459C>T	p.Tyr153Tyr	synonymous_variant	4/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.498C>T		non_coding_transcript_exon_variant	4/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.498C>T		non_coding_transcript_exon_variant	4/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 730 AN: 152116 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.0311

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0430

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00613 AC: 1423 AN: 232222 Hom.: 16 AF XY: 0.00597 AC XY: 751 AN XY: 125732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000914

Gnomad ASJ exome AF: 0.00600

Gnomad EAS exome AF: 0.0274

Gnomad SAS exome AF: 0.00143

Gnomad FIN exome AF: 0.0355

Gnomad NFE exome AF: 0.000993

Gnomad OTH exome AF: 0.00503

GnomAD4 exome AF: 0.00230 AC: 3347 AN: 1452142 Hom.: 40 Cov.: 34 AF XY: 0.00226 AC XY: 1631 AN XY: 721216

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000690

Gnomad4 ASJ exome AF: 0.00733

Gnomad4 EAS exome AF: 0.0210

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.0321

Gnomad4 NFE exome AF: 0.000274

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.00479 AC: 729 AN: 152234 Hom.: 10 Cov.: 33 AF XY: 0.00683 AC XY: 508 AN XY: 74428

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.0309

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0430

Gnomad4 NFE AF: 0.000927

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00189

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Significance: 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.3
DANN	Benign	0.96

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: rs58142268; hg19: chr16-1245518;