rs3751889

Variant names:

• chr16-1220055-T-C
• rs3751889
• NM_021098.3:c.6123T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-1220055-T-C
• chr16-1220055-T-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The ENST00000711482.1(CACNA1H):​c.6121+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0274 in 1,427,114 control chromosomes in the GnomAD database, including 1,083 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (435 hom., cov: 34)
  • Exomes 𝑓: 0.024 (648 hom.)
• Consequence: CACNA1H ENST00000711482.1 splice_donor, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.98
• Publications: 11 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 9.4, offset of 14, new splice context is: ccgGTgagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 16-1220055-T-C is Benign according to our data. Variant chr16-1220055-T-C is described in ClinVar as Benign. ClinVar VariationId is 96014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000711482.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.6123T>C	p.Gly2041Gly	synonymous	Exon 35 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.6105T>C	p.Gly2035Gly	synonymous	Exon 34 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.6123T>C	p.Gly2041Gly	synonymous	Exon 35 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.6138T>C	p.Gly2046Gly	synonymous	Exon 34 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.6108T>C	p.Gly2036Gly	synonymous	Exon 34 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.0531 AC: 8074 AN: 152062 Hom.: 426 Cov.: 34

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00881

Gnomad AMR AF: 0.0354

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.0965

Gnomad SAS AF: 0.0424

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0440

GnomAD2 exomes AF: 0.0325 AC: 2972 AN: 91576 AF XY: 0.0294

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0462

Gnomad ASJ exome AF: 0.00684

Gnomad EAS exome AF: 0.0769

Gnomad FIN exome AF: 0.00933

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0243 AC: 30971 AN: 1274936 Hom.: 648 Cov.: 30 AF XY: 0.0241 AC XY: 14889 AN XY: 618304

African (AFR) AF: 0.138 AC: 3500 AN: 25370

American (AMR) AF: 0.0438 AC: 861 AN: 19658

Ashkenazi Jewish (ASJ) AF: 0.00623 AC: 111 AN: 17826

East Asian (EAS) AF: 0.0777 AC: 2405 AN: 30938

South Asian (SAS) AF: 0.0368 AC: 1989 AN: 54086

European-Finnish (FIN) AF: 0.0101 AC: 465 AN: 45862

Middle Eastern (MID) AF: 0.0240 AC: 123 AN: 5116

European-Non Finnish (NFE) AF: 0.0194 AC: 19821 AN: 1023560

Other (OTH) AF: 0.0323 AC: 1696 AN: 52520

GnomAD4 genome AF: 0.0533 AC: 8106 AN: 152178 Hom.: 435 Cov.: 34 AF XY: 0.0523 AC XY: 3890 AN XY: 74398

African (AFR) AF: 0.131 AC: 5419 AN: 41488

American (AMR) AF: 0.0353 AC: 541 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.0969 AC: 501 AN: 5170

South Asian (SAS) AF: 0.0422 AC: 204 AN: 4830

European-Finnish (FIN) AF: 0.00791 AC: 84 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1236 AN: 67986

Other (OTH) AF: 0.0431 AC: 91 AN: 2112

Alfa AF: 0.0271 Hom.: 153

Bravo AF: 0.0583

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.032
DANN	Benign	0.44
PhyloP100		-4.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3751889; hg19: chr16-1270055; COSMIC: COSV52355369; COSMIC: COSV52355369;