rs59091981

Variant names:

• chr16-1200708-C-A
• rs59091981
• NM_021098.3:c.1120-8C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1200708-C-A
• chr16-1200708-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021098.3(CACNA1H):​c.1120-8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,413,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.004134
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

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>A		splice_region intron	N/A	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.1120-8C>A		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>A		splice_region intron	N/A	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.1120-8C>A		splice_region intron	N/A	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.1120-8C>A		splice_region intron	N/A	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1413282 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 698920

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

African (AFR) AF: 0.00 AC: 0 AN: 32062

American (AMR) AF: 0.00 AC: 0 AN: 37274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25338

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36648

South Asian (SAS) AF: 0.00 AC: 0 AN: 81280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087200

Other (OTH) AF: 0.00 AC: 0 AN: 58622

⚠️ 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 Cov.: 32

Alfa AF: 0.00 Hom.: 17

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.4
DANN	Benign	0.31
PhyloP100		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0041
dbscSNV1_RF	Benign	0.11
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;