rs61018135

Variant names:

• chr16-1204076-C-T
• rs61018135
• NM_021098.3:c.2069C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.2069C>T​(p.Ala690Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,604,682 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). Synonymous variant affecting the same amino acid position (i.e. A690A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.61
• 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2558084).
• BP6: Variant 16-1204076-C-T is Benign according to our data. Variant chr16-1204076-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529604.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000525 (762/1452330) while in subpopulation NFE AF = 0.000645 (715/1108336). AF 95% confidence interval is 0.000605. There are 0 homozygotes in GnomAdExome4. There are 374 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 29 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.2069C>T	p.Ala690Val	missense	Exon 10 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.2069C>T	p.Ala690Val	missense	Exon 10 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.2069C>T	p.Ala690Val	missense	Exon 10 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.2069C>T	p.Ala690Val	missense	Exon 10 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.2069C>T	p.Ala690Val	missense	Exon 10 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 29 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000964

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: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000248 AC: 57 AN: 230018 AF XY: 0.000214

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.000180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000508

Gnomad NFE exome AF: 0.000447

Gnomad OTH exome AF: 0.000351

GnomAD4 exome AF: 0.000525 AC: 762 AN: 1452330 Hom.: 0 Cov.: 32 AF XY: 0.000518 AC XY: 374 AN XY: 721634

African (AFR) AF: 0.0000300 AC: 1 AN: 33316

American (AMR) AF: 0.000137 AC: 6 AN: 43860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25922

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39356

South Asian (SAS) AF: 0.0000355 AC: 3 AN: 84612

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000645 AC: 715 AN: 1108336

Other (OTH) AF: 0.000583 AC: 35 AN: 60058

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74500

African (AFR) AF: 0.0000962 AC: 4 AN: 41600

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000200 AC: 24

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.021	D
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.24
MVP		0.95
ClinPred		0.068	T
GERP RS		4.0
Varity_R		0.16
gMVP		0.25
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs61018135; hg19: chr16-1254076; COSMIC: COSV61985169; COSMIC: COSV61985169;