16-1220443-T-C

Variant names:

• chr16-1220443-T-C
• rs746446797
• NM_021098.3:c.6511T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_021098.3(CACNA1H):​c.6511T>C​(p.Trp2171Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,387,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W2171C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.680
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085768014).
• BP6: Variant 16-1220443-T-C is Benign according to our data. Variant chr16-1220443-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 529556.Status of the report is criteria_provided_single_submitter, 1 stars.

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.6511T>C	p.Trp2171Arg	missense	Exon 35 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.6493T>C	p.Trp2165Arg	missense	Exon 34 of 34	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.6511T>C	p.Trp2171Arg	missense	Exon 35 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.6526T>C	p.Trp2176Arg	missense	Exon 34 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.6496T>C	p.Trp2166Arg	missense	Exon 34 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 2 AN: 166954 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1387080 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 685516

African (AFR) AF: 0.00 AC: 0 AN: 29962

American (AMR) AF: 0.00 AC: 0 AN: 30018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20910

East Asian (EAS) AF: 0.00 AC: 0 AN: 38614

South Asian (SAS) AF: 0.00 AC: 0 AN: 73418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5370

European-Non Finnish (NFE) AF: 0.00000277 AC: 3 AN: 1083646

Other (OTH) AF: 0.00 AC: 0 AN: 57052

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Dec 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	0.0047	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	1.1
DANN	Benign	0.33
DEOGEN2	Benign	0.067	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.086	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-0.68
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.26
Sift	Benign	0.54	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.014
MutPred		0.21		Gain of solvent accessibility (P = 0.0137)
MVP		0.33
ClinPred		0.020	T
GERP RS		-1.9
Varity_R		0.064
gMVP		0.044
Mutation Taster		=97/3	polymorphism

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: rs746446797; hg19: chr16-1270443;