16-1219113-C-T

Variant names:

• chr16-1219113-C-T
• rs753241781
• NM_021098.3:c.6031C>T
• CACNA1H p.Arg2011Trp

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_021098.3(CACNA1H):​c.6031C>T​(p.Arg2011Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,543,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2011Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0520
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27232045).
• BP6: Variant 16-1219113-C-T is Benign according to our data. Variant chr16-1219113-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460157.
• BS2: High AC in GnomAd4 at 10 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.6031C>T	p.Arg2011Trp	missense	Exon 34 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.6013C>T	p.Arg2005Trp	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.6031C>T	p.Arg2011Trp	missense	Exon 34 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.6046C>T	p.Arg2016Trp	missense	Exon 33 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.6016C>T	p.Arg2006Trp	missense	Exon 33 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152158 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 18 AN: 145658 AF XY: 0.000102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000146

Gnomad OTH exome AF: 0.000238

GnomAD4 exome AF: 0.000162 AC: 226 AN: 1390908 Hom.: 0 Cov.: 34 AF XY: 0.000158 AC XY: 108 AN XY: 685248

African (AFR) AF: 0.000254 AC: 8 AN: 31470

American (AMR) AF: 0.000339 AC: 12 AN: 35386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24846

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35574

South Asian (SAS) AF: 0.000203 AC: 16 AN: 78784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46632

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5660

European-Non Finnish (NFE) AF: 0.000170 AC: 183 AN: 1074886

Other (OTH) AF: 0.0000867 AC: 5 AN: 57670

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152158 Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6 AN XY: 74332

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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	0.13
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.052
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.16
gMVP		0.42
Mutation Taster		=92/8	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs753241781;

hg19: chr16-1269113;

COSMIC: COSV99326742;

COSMIC: COSV99326742;