NM_021098.3:c.2931C>T

Variant names:

• chr16-1207298-C-T
• rs376470846
• NM_021098.3:c.2931C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_021098.3(CACNA1H):​c.2931C>T​(p.Asn977Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000429 in 1,610,150 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 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.367
• Publications: 0 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

ENSG00000261294 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 16-1207298-C-T is Benign according to our data. Variant chr16-1207298-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 529644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.367 with no splicing effect.
• BS2: High AC in GnomAd4 at 16 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.2931C>T	p.Asn977Asn	synonymous	Exon 14 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.2931C>T	p.Asn977Asn	synonymous	Exon 14 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.2931C>T	p.Asn977Asn	synonymous	Exon 14 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.2931C>T	p.Asn977Asn	synonymous	Exon 14 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.2931C>T	p.Asn977Asn	synonymous	Exon 14 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152040 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000331 AC: 8 AN: 241824 AF XY: 0.0000228

Gnomad AFR exome AF: 0.000205

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1458110 Hom.: 0 Cov.: 33 AF XY: 0.0000345 AC XY: 25 AN XY: 725094

African (AFR) AF: 0.000419 AC: 14 AN: 33416

American (AMR) AF: 0.0000226 AC: 1 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39616

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52578

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

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1110404

Other (OTH) AF: 0.0000498 AC: 3 AN: 60260

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152040 Hom.: 0 Cov.: 30 AF XY: 0.0000943 AC XY: 7 AN XY: 74252

African (AFR) AF: 0.000290 AC: 12 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	-0.38
CADD	Benign	4.4
DANN	Benign	0.93
PhyloP100		-0.37

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs376470846; hg19: chr16-1257298; COSMIC: COSV100671249; COSMIC: COSV100671249;