rs72552054

Variant names:

• chr16-1218979-C-T
• rs72552054
• NM_021098.3:c.5897C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1218979-C-T
• chr16-1218979-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.5897C>T​(p.Ala1966Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,550,154 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (29 hom., cov: 31)
  • Exomes 𝑓: 0.022 (402 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.978
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041008294).
• BP6: Variant 16-1218979-C-T is Benign according to our data. Variant chr16-1218979-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0153 (2328/152242) while in subpopulation SAS AF = 0.0271 (131/4834). AF 95% confidence interval is 0.0233. There are 29 homozygotes in GnomAd4. There are 1169 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2328 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.5897C>T	p.Ala1966Val	missense	Exon 34 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.5879C>T	p.Ala1960Val	missense	Exon 33 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.5897C>T	p.Ala1966Val	missense	Exon 34 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.5912C>T	p.Ala1971Val	missense	Exon 33 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000565831.7	TSL:1	c.5879C>T	p.Ala1960Val	missense	Exon 33 of 34	ENSP00000455840.1	O95180-2

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2327 AN: 152124 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.00394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0170 AC: 2628 AN: 154172 AF XY: 0.0176

Gnomad AFR exome AF: 0.00401

Gnomad AMR exome AF: 0.00743

Gnomad ASJ exome AF: 0.00768

Gnomad EAS exome AF: 0.0000922

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0239

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0223 AC: 31200 AN: 1397912 Hom.: 402 Cov.: 33 AF XY: 0.0223 AC XY: 15400 AN XY: 689506

African (AFR) AF: 0.00298 AC: 94 AN: 31594

American (AMR) AF: 0.00801 AC: 286 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00870 AC: 219 AN: 25164

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35734

South Asian (SAS) AF: 0.0235 AC: 1858 AN: 79228

European-Finnish (FIN) AF: 0.0207 AC: 995 AN: 48054

Middle Eastern (MID) AF: 0.0108 AC: 61 AN: 5636

European-Non Finnish (NFE) AF: 0.0246 AC: 26557 AN: 1078830

Other (OTH) AF: 0.0195 AC: 1129 AN: 57982

GnomAD4 genome AF: 0.0153 AC: 2328 AN: 152242 Hom.: 29 Cov.: 31 AF XY: 0.0157 AC XY: 1169 AN XY: 74430

African (AFR) AF: 0.00392 AC: 163 AN: 41540

American (AMR) AF: 0.0108 AC: 165 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.0271 AC: 131 AN: 4834

European-Finnish (FIN) AF: 0.0211 AC: 224 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0234 AC: 1593 AN: 68000

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.0142 Hom.: 8

Bravo AF: 0.0132

TwinsUK AF: 0.0256 AC: 95

ALSPAC AF: 0.0252 AC: 97

ESP6500AA AF: 0.00475 AC: 16

ESP6500EA AF: 0.0202 AC: 133

ExAC AF: 0.0114 AC: 435

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Benign	0.79
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0041	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.98
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.29
Sift	Benign	0.30	T
Sift4G	Benign	0.51	T
Polyphen		0.0010	B
Vest4		0.045
ClinPred		0.00072	T
GERP RS		3.5
La Branchor		0.40
Varity_R		0.029
gMVP		0.19
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs72552054; hg19: chr16-1268979;