chr16-1217977-C-T

Variant names:

• chr16-1217977-C-T
• rs567978624
• NM_021098.3:c.5382C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_021098.3(CACNA1H):​c.5382C>T​(p.Phe1794Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,605,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.79
• 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 16-1217977-C-T is Benign according to our data. Variant chr16-1217977-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 460142.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.79 with no splicing effect.
• BS2: High AC in GnomAd4 at 8 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.5382C>T	p.Phe1794Phe	synonymous	Exon 32 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.5364C>T	p.Phe1788Phe	synonymous	Exon 31 of 34	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.5382C>T	p.Phe1794Phe	synonymous	Exon 32 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.5397C>T	p.Phe1799Phe	synonymous	Exon 31 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.5400C>T	p.Phe1800Phe	synonymous	Exon 31 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152250 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000386 AC: 9 AN: 233362 AF XY: 0.0000315

Gnomad AFR exome AF: 0.000145

Gnomad AMR exome AF: 0.0000903

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1452760 Hom.: 0 Cov.: 32 AF XY: 0.00000831 AC XY: 6 AN XY: 721860

African (AFR) AF: 0.000120 AC: 4 AN: 33300

American (AMR) AF: 0.0000456 AC: 2 AN: 43904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39274

South Asian (SAS) AF: 0.00 AC: 0 AN: 84602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1108514

Other (OTH) AF: 0.0000500 AC: 3 AN: 60044

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152368 Hom.: 0 Cov.: 34 AF XY: 0.0000805 AC XY: 6 AN XY: 74514

African (AFR) AF: 0.000120 AC: 5 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.9
DANN	Benign	0.94
PhyloP100		-1.8

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs567978624; hg19: chr16-1267977; COSMIC: COSV52356872; COSMIC: COSV52356872;