rs199547941

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-1219971-G-A
• chr16-1219971-G-C
• chr16-1219971-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_021098.3(CACNA1H):​c.6049-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,289,448 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 0.000085 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CACNA1H NM_021098.3 intron
• Scores: Splicing: ADA: 0.0003803
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.459
• 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-1219971-G-A is Benign according to our data. Variant chr16-1219971-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 460159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 13 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.6049-10G>A		intron	N/A	NP_066921.2
	CACNA1H	NM_001005407.2		c.6031-10G>A		intron	N/A	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.6049-10G>A		intron	N/A	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.6064-10G>A		intron	N/A	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.6034-10G>A		intron	N/A	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152054 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000593 AC: 3 AN: 50598 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000438

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000740

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000171 AC: 194 AN: 1137276 Hom.: 0 Cov.: 30 AF XY: 0.000172 AC XY: 93 AN XY: 540940

African (AFR) AF: 0.00 AC: 0 AN: 23732

American (AMR) AF: 0.00 AC: 0 AN: 11186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15060

East Asian (EAS) AF: 0.00 AC: 0 AN: 27638

South Asian (SAS) AF: 0.00 AC: 0 AN: 25790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4576

European-Non Finnish (NFE) AF: 0.000200 AC: 189 AN: 944882

Other (OTH) AF: 0.000109 AC: 5 AN: 45986

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152172 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74394

African (AFR) AF: 0.000169 AC: 7 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000869

ClinVar

ClinVar submissions as Germline

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	-0.83
CADD	Benign	3.5
DANN	Benign	0.43
PhyloP100		-0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00038
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs199547941; hg19: chr16-1269971;