16-1219095-C-T

Variant names:

• chr16-1219095-C-T
• rs72552056
• NM_021098.3:c.6013C>T

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.6013C>T​(p.Arg2005Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0595 in 1,547,162 control chromosomes in the GnomAD database, including 3,216 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. R2005S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.047 (245 hom., cov: 33)
  • Exomes 𝑓: 0.061 (2971 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.198
• Publications: 14 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=0.0018978119).
• BP6: Variant 16-1219095-C-T is Benign according to our data. Variant chr16-1219095-C-T is described in ClinVar as Benign. ClinVar VariationId is 585654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0728 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.6013C>T	p.Arg2005Cys	missense	Exon 34 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.5995C>T	p.Arg1999Cys	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.6013C>T	p.Arg2005Cys	missense	Exon 34 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.6028C>T	p.Arg2010Cys	missense	Exon 33 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.5998C>T	p.Arg2000Cys	missense	Exon 33 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 7149 AN: 152178 Hom.: 244 Cov.: 33

Gnomad AFR AF: 0.00944

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0436

Gnomad ASJ AF: 0.0910

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0787

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0672

Gnomad OTH AF: 0.0578

GnomAD2 exomes AF: 0.0566 AC: 8457 AN: 149494 AF XY: 0.0607

Gnomad AFR exome AF: 0.00750

Gnomad AMR exome AF: 0.0330

Gnomad ASJ exome AF: 0.0954

Gnomad EAS exome AF: 0.000186

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0664

Gnomad OTH exome AF: 0.0695

GnomAD4 exome AF: 0.0609 AC: 84965 AN: 1394866 Hom.: 2971 Cov.: 35 AF XY: 0.0620 AC XY: 42610 AN XY: 687636

African (AFR) AF: 0.00831 AC: 262 AN: 31546

American (AMR) AF: 0.0339 AC: 1205 AN: 35558

Ashkenazi Jewish (ASJ) AF: 0.0944 AC: 2366 AN: 25066

East Asian (EAS) AF: 0.000196 AC: 7 AN: 35648

South Asian (SAS) AF: 0.0851 AC: 6725 AN: 79062

European-Finnish (FIN) AF: 0.0513 AC: 2424 AN: 47280

Middle Eastern (MID) AF: 0.0835 AC: 474 AN: 5678

European-Non Finnish (NFE) AF: 0.0631 AC: 67983 AN: 1077204

Other (OTH) AF: 0.0609 AC: 3519 AN: 57824

GnomAD4 genome AF: 0.0470 AC: 7151 AN: 152296 Hom.: 245 Cov.: 33 AF XY: 0.0455 AC XY: 3391 AN XY: 74462

African (AFR) AF: 0.00941 AC: 391 AN: 41552

American (AMR) AF: 0.0436 AC: 667 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0910 AC: 316 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.0794 AC: 383 AN: 4824

European-Finnish (FIN) AF: 0.0490 AC: 520 AN: 10622

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0672 AC: 4570 AN: 68012

Other (OTH) AF: 0.0568 AC: 120 AN: 2114

Alfa AF: 0.0594 Hom.: 323

Bravo AF: 0.0420

TwinsUK AF: 0.0618 AC: 229

ALSPAC AF: 0.0579 AC: 223

ESP6500AA AF: 0.00739 AC: 25

ESP6500EA AF: 0.0536 AC: 389

ExAC AF: 0.0289 AC: 2059

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	8.9
DANN	Benign	0.93
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0019	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.20
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.26
Sift	Benign	0.052	T
Sift4G	Uncertain	0.043	D
Polyphen		0.0010	B
Vest4		0.12
ClinPred		0.029	T
GERP RS		-1.9
Varity_R		0.17
gMVP		0.31
Mutation Taster		=97/3	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: rs72552056; hg19: chr16-1269095; COSMIC: COSV52359202; COSMIC: COSV52359202;