16-1210376-C-T

Variant names:

• chr16-1210376-C-T
• rs374262237
• NM_021098.3:c.3852C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_021098.3(CACNA1H):​c.3852C>T​(p.Arg1284Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,552,204 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: 𝑓 0.000020 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000093 (0 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.19

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3852C>T	p.Arg1284Arg	synonymous_variant	Exon 19 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3852C>T	p.Arg1284Arg	synonymous_variant	Exon 19 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.3852C>T	p.Arg1284Arg	synonymous_variant	Exon 18 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.3813C>T	p.Arg1271Arg	synonymous_variant	Exon 19 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.75C>T	p.Arg25Arg	synonymous_variant	Exon 2 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.75C>T	p.Arg25Arg	synonymous_variant	Exon 2 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.75C>T	p.Arg25Arg	synonymous_variant	Exon 2 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000637236.2	n.215C>T		non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.3852C>T		non_coding_transcript_exon_variant	Exon 19 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1765C>T		non_coding_transcript_exon_variant	Exon 19 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*1765C>T		3_prime_UTR_variant	Exon 19 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150698 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000490

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000170 AC: 3 AN: 176064 Hom.: 0 AF XY: 0.0000316 AC XY: 3 AN XY: 95068

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000262

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000928 AC: 13 AN: 1401390 Hom.: 0 Cov.: 32 AF XY: 0.0000130 AC XY: 9 AN XY: 693532

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000395

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000923

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150814 Hom.: 0 Cov.: 26 AF XY: 0.0000272 AC XY: 2 AN XY: 73586

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.1
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs374262237; hg19: chr16-1260376;