rs772769994

Positions:

• chr16-1211178-C-A
• chr16-1211178-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_021098.3(CACNA1H):​c.4234C>A​(p.Arg1412Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,434 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: 35)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP7: Synonymous conserved (PhyloP=2.13 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4234C>A	p.Arg1412Arg	synonymous_variant	22/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4234C>A	p.Arg1412Arg	synonymous_variant	22/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4234C>A	p.Arg1412Arg	synonymous_variant	21/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4195C>A	p.Arg1399Arg	synonymous_variant	22/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.457C>A	p.Arg153Arg	synonymous_variant	5/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.457C>A	p.Arg153Arg	synonymous_variant	5/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.457C>A	p.Arg153Arg	synonymous_variant	5/17	1		ENSP00000454581.2
CACNA1H	ENST00000637236.2	n.*204C>A		non_coding_transcript_exon_variant	6/6	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4234C>A		non_coding_transcript_exon_variant	22/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2147C>A		non_coding_transcript_exon_variant	22/35	5		ENSP00000491488.1
CACNA1H	ENST00000637236.2	n.*204C>A		3_prime_UTR_variant	6/6	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1	n.*2147C>A		3_prime_UTR_variant	22/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 247848 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134910

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460434 Hom.: 0 Cov.: 50 AF XY: 0.00 AC XY: 0 AN XY: 726508

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.5
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs772769994; hg19: chr16-1261178;