rs373353512

Positions:

• chr16-1218398-C-G
• chr16-1218398-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_021098.3(CACNA1H):​c.5634C>G​(p.Ala1878Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000427 in 1,405,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -8.63

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP7: Synonymous conserved (PhyloP=-8.63 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5634C>G	p.Ala1878Ala	synonymous_variant	33/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5634C>G	p.Ala1878Ala	synonymous_variant	33/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5616C>G	p.Ala1872Ala	synonymous_variant	31/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5595C>G	p.Ala1865Ala	synonymous_variant	33/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1872C>G	p.Ala624Ala	synonymous_variant	15/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1857C>G	p.Ala619Ala	synonymous_variant	16/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1839C>G	p.Ala613Ala	synonymous_variant	15/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*715C>G		non_coding_transcript_exon_variant	33/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3485C>G		non_coding_transcript_exon_variant	33/35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*715C>G		3_prime_UTR_variant	33/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3485C>G		3_prime_UTR_variant	33/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000602 AC: 1 AN: 166180 Hom.: 0 AF XY: 0.0000113 AC XY: 1 AN XY: 88122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000433

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000427 AC: 6 AN: 1405602 Hom.: 0 Cov.: 33 AF XY: 0.00000576 AC XY: 4 AN XY: 693952

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.017
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs373353512; hg19: chr16-1268398;