16-1219971-G-C

Variant names:

• chr16-1219971-G-C
• rs199547941
• NM_021098.3:c.6049-10G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021098.3(CACNA1H):​c.6049-10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000233 in 1,289,332 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 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: CACNA1H NM_021098.3 intron
• Scores: Splicing: ADA: 0.00003359
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6049-10G>C		intron_variant	Intron 34 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6049-10G>C		intron_variant	Intron 34 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.6031-10G>C		intron_variant	Intron 32 of 32	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.6010-10G>C		intron_variant	Intron 34 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2287-10G>C		intron_variant	Intron 16 of 16	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2239-10G>C		intron_variant	Intron 17 of 17	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2221-10G>C		intron_variant	Intron 16 of 16	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1097-10G>C		intron_variant	Intron 34 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3867-10G>C		intron_variant	Intron 34 of 34	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152054 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.79e-7 AC: 1 AN: 1137278 Hom.: 0 Cov.: 30 AF XY: 0.00000185 AC XY: 1 AN XY: 540942

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: 0.00000106

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152054 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74266

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.070		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: rs199547941; hg19: chr16-1269971;