16-1195916-C-T

Variant names:

• chr16-1195916-C-T
• rs35509671
• NM_021098.3:c.546-10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.546-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,610,874 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (94 hom.)
• Consequence: CACNA1H NM_021098.3 intron
• Scores: Splicing: ADA: 0.00001854
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.434
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• hyperaldosteronism, familial, type IV

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, childhood absence, susceptibility to, 6

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-1195916-C-T is Benign according to our data. Variant chr16-1195916-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0127 (1934/152342) while in subpopulation EAS AF = 0.047 (243/5166). AF 95% confidence interval is 0.0422. There are 24 homozygotes in GnomAd4. There are 988 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1934 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.546-10C>T		intron	N/A	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.546-10C>T		intron	N/A	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.546-10C>T		intron	N/A	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.546-10C>T		intron	N/A	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.546-10C>T		intron	N/A	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1936 AN: 152224 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0471

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00903

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0124 AC: 3075 AN: 247466 AF XY: 0.0108

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.0330

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.0488

Gnomad FIN exome AF: 0.00993

Gnomad NFE exome AF: 0.000744

Gnomad OTH exome AF: 0.00830

GnomAD4 exome AF: 0.00407 AC: 5939 AN: 1458532 Hom.: 94 Cov.: 32 AF XY: 0.00395 AC XY: 2870 AN XY: 725692

African (AFR) AF: 0.0302 AC: 1009 AN: 33426

American (AMR) AF: 0.0309 AC: 1382 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 38 AN: 26106

East Asian (EAS) AF: 0.0366 AC: 1452 AN: 39688

South Asian (SAS) AF: 0.00796 AC: 686 AN: 86206

European-Finnish (FIN) AF: 0.00880 AC: 462 AN: 52482

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5766

European-Non Finnish (NFE) AF: 0.000442 AC: 491 AN: 1109884

Other (OTH) AF: 0.00659 AC: 397 AN: 60264

GnomAD4 genome AF: 0.0127 AC: 1934 AN: 152342 Hom.: 24 Cov.: 33 AF XY: 0.0133 AC XY: 988 AN XY: 74478

African (AFR) AF: 0.0292 AC: 1215 AN: 41580

American (AMR) AF: 0.0158 AC: 242 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.0470 AC: 243 AN: 5166

South Asian (SAS) AF: 0.00807 AC: 39 AN: 4830

European-Finnish (FIN) AF: 0.00903 AC: 96 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68038

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.00773 Hom.: 6

Bravo AF: 0.0150

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CACNA1H-related disorder (1)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.5
DANN	Benign	0.69
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs35509671; hg19: chr16-1245916;