16-1210360-G-C

Variant names:

• chr16-1210360-G-C
• rs377030217
• NM_021098.3:c.3846-10G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_021098.3(CACNA1H):​c.3846-10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (0 hom., cov: 0)
  • Exomes 𝑓: 0.23 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1H NM_021098.3 intron
• Scores: Splicing: ADA: 0.00001511
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.79
• Publications: 1 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-1210360-G-C is Benign according to our data. Variant chr16-1210360-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 706988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.3846-10G>C		intron	N/A	NP_066921.2
	CACNA1H	NM_001005407.2		c.3846-10G>C		intron	N/A	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.3846-10G>C		intron	N/A	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.3846-10G>C		intron	N/A	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.3846-10G>C		intron	N/A	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 1643 AN: 10774 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.0455

Gnomad SAS AF: 0.0738

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.239 AC: 9576 AN: 40034 AF XY: 0.234

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.337

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.287

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.225 AC: 25156 AN: 111784 Hom.: 0 Cov.: 0 AF XY: 0.226 AC XY: 13637 AN XY: 60390

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.273 AC: 899 AN: 3290

American (AMR) AF: 0.348 AC: 2637 AN: 7576

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 714 AN: 3492

East Asian (EAS) AF: 0.190 AC: 715 AN: 3768

South Asian (SAS) AF: 0.273 AC: 4295 AN: 15712

European-Finnish (FIN) AF: 0.170 AC: 777 AN: 4558

Middle Eastern (MID) AF: 0.0941 AC: 76 AN: 808

European-Non Finnish (NFE) AF: 0.205 AC: 13904 AN: 67708

Other (OTH) AF: 0.234 AC: 1139 AN: 4872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.152 AC: 1644 AN: 10828 Hom.: 0 Cov.: 0 AF XY: 0.134 AC XY: 776 AN XY: 5798

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.146 AC: 435 AN: 2978

American (AMR) AF: 0.0663 AC: 111 AN: 1674

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 38 AN: 176

East Asian (EAS) AF: 0.0455 AC: 12 AN: 264

South Asian (SAS) AF: 0.0732 AC: 18 AN: 246

European-Finnish (FIN) AF: 0.143 AC: 129 AN: 900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 18

European-Non Finnish (NFE) AF: 0.198 AC: 857 AN: 4334

Other (OTH) AF: 0.181 AC: 38 AN: 210

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000246 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 20, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.36
PhyloP100		-2.8
PromoterAI		0.018	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.022
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: rs377030217; hg19: chr16-1260360;