rs1054645

Variant names:

• chr16-1220162-G-A
• rs1054645
• NM_021098.3:c.6230G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1220162-G-A
• chr16-1220162-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021098.3(CACNA1H):​c.6230G>A​(p.Arg2077His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 1,523,120 control chromosomes in the GnomAD database, including 285,545 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2077C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.65 (32651 hom., cov: 35)
  • Exomes 𝑓: 0.60 (252894 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.784
• Publications: 49 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)
• 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=8.9449054E-7).
• BP6: Variant 16-1220162-G-A is Benign according to our data. Variant chr16-1220162-G-A is described in ClinVar as Benign. ClinVar VariationId is 96016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

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.6230G>A	p.Arg2077His	missense	Exon 35 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.6212G>A	p.Arg2071His	missense	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.6230G>A	p.Arg2077His	missense	Exon 35 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.6245G>A	p.Arg2082His	missense	Exon 34 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.6215G>A	p.Arg2072His	missense	Exon 34 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.650 AC: 98790 AN: 152052 Hom.: 32623 Cov.: 35

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.655

GnomAD2 exomes AF: 0.657 AC: 109910 AN: 167372 AF XY: 0.646

Gnomad AFR exome AF: 0.705

Gnomad AMR exome AF: 0.747

Gnomad ASJ exome AF: 0.709

Gnomad EAS exome AF: 0.895

Gnomad FIN exome AF: 0.701

Gnomad NFE exome AF: 0.595

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.604 AC: 827558 AN: 1370950 Hom.: 252894 Cov.: 70 AF XY: 0.602 AC XY: 405972 AN XY: 674462

African (AFR) AF: 0.709 AC: 20105 AN: 28372

American (AMR) AF: 0.735 AC: 24437 AN: 33246

Ashkenazi Jewish (ASJ) AF: 0.697 AC: 14833 AN: 21278

East Asian (EAS) AF: 0.901 AC: 32252 AN: 35778

South Asian (SAS) AF: 0.561 AC: 40542 AN: 72308

European-Finnish (FIN) AF: 0.690 AC: 33565 AN: 48680

Middle Eastern (MID) AF: 0.702 AC: 3785 AN: 5390

European-Non Finnish (NFE) AF: 0.582 AC: 622803 AN: 1069526

Other (OTH) AF: 0.625 AC: 35236 AN: 56372

GnomAD4 genome AF: 0.650 AC: 98862 AN: 152170 Hom.: 32651 Cov.: 35 AF XY: 0.657 AC XY: 48845 AN XY: 74366

African (AFR) AF: 0.699 AC: 29030 AN: 41522

American (AMR) AF: 0.703 AC: 10758 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 2469 AN: 3472

East Asian (EAS) AF: 0.876 AC: 4513 AN: 5152

South Asian (SAS) AF: 0.559 AC: 2692 AN: 4820

European-Finnish (FIN) AF: 0.710 AC: 7535 AN: 10610

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.585 AC: 39742 AN: 67968

Other (OTH) AF: 0.660 AC: 1396 AN: 2114

Alfa AF: 0.612 Hom.: 76473

Bravo AF: 0.659

TwinsUK AF: 0.570 AC: 2113

ALSPAC AF: 0.589 AC: 2269

ESP6500AA AF: 0.728 AC: 2894

ESP6500EA AF: 0.608 AC: 5031

ExAC AF: 0.627 AC: 73990

Asia WGS AF: 0.720 AC: 2501 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Epilepsy, childhood absence, susceptibility to, 6 (2)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.74
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.11	N
PhyloP100		-0.78
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.033
Sift	Benign	0.59	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.033
ClinPred		0.0018	T
GERP RS		0.76
Varity_R		0.022
gMVP		0.20
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1054645; hg19: chr16-1270162; COSMIC: COSV52354598; COSMIC: COSV52354598;