16-1200708-C-T

Variant names:

• chr16-1200708-C-T
• rs59091981
• NM_021098.3:c.1120-8C>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.1120-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,565,138 control chromosomes in the GnomAD database, including 139 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (12 hom., cov: 32)
  • Exomes 𝑓: 0.012 (127 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.00007083
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.01
• 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: G2P, Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC124903623 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-1200708-C-T is Benign according to our data. Variant chr16-1200708-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00913 (1387/151962) while in subpopulation NFE AF = 0.0147 (997/68022). AF 95% confidence interval is 0.0139. There are 12 homozygotes in GnomAd4. There are 638 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1387 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.1120-8C>T		splice_region intron	N/A	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.1120-8C>T		splice_region 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.1120-8C>T		splice_region intron	N/A	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.1120-8C>T		splice_region intron	N/A	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.1120-8C>T		splice_region intron	N/A	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.00914 AC: 1388 AN: 151844 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00873 AC: 1522 AN: 174388 AF XY: 0.00918

Gnomad AFR exome AF: 0.00268

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.00183

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00427

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.0120 AC: 16976 AN: 1413176 Hom.: 127 Cov.: 33 AF XY: 0.0120 AC XY: 8380 AN XY: 698874

African (AFR) AF: 0.00178 AC: 57 AN: 32062

American (AMR) AF: 0.00716 AC: 267 AN: 37274

Ashkenazi Jewish (ASJ) AF: 0.00205 AC: 52 AN: 25338

East Asian (EAS) AF: 0.00 AC: 0 AN: 36648

South Asian (SAS) AF: 0.00737 AC: 599 AN: 81276

European-Finnish (FIN) AF: 0.00407 AC: 201 AN: 49332

Middle Eastern (MID) AF: 0.0109 AC: 60 AN: 5524

European-Non Finnish (NFE) AF: 0.0139 AC: 15149 AN: 1087104

Other (OTH) AF: 0.0101 AC: 591 AN: 58618

GnomAD4 genome AF: 0.00913 AC: 1387 AN: 151962 Hom.: 12 Cov.: 32 AF XY: 0.00859 AC XY: 638 AN XY: 74260

African (AFR) AF: 0.00231 AC: 96 AN: 41554

American (AMR) AF: 0.0132 AC: 197 AN: 14978

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4824

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 997 AN: 68022

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.0124 Hom.: 17

Bravo AF: 0.00879

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	CACNA1H-related disorder (1)
-	-	1	Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV (1)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.32
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs59091981; hg19: chr16-1250708;