rs948561024

Variant names:

• chr16-1153750-G-A
• rs948561024
• NM_021098.3:c.13G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1153750-G-A
• chr16-1153750-G-C
• chr16-1153750-G-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.13G>A​(p.Ala5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,212,022 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.369
• Publications: 1 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=0.099538594).
• BP6: Variant 16-1153750-G-A is Benign according to our data. Variant chr16-1153750-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 800247.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000536 (81/151074) while in subpopulation AFR AF = 0.00184 (76/41342). AF 95% confidence interval is 0.00151. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 81 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.13G>A	p.Ala5Thr	missense	Exon 2 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.13G>A	p.Ala5Thr	missense	Exon 2 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.13G>A	p.Ala5Thr	missense	Exon 2 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.13G>A	p.Ala5Thr	missense	Exon 2 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.13G>A	p.Ala5Thr	missense	Exon 2 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.000537 AC: 81 AN: 150972 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.0000148

Gnomad OTH AF: 0.000965

GnomAD2 exomes AF: 0.00 AC: 0 AN: 454 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 53 AN: 1060948 Hom.: 0 Cov.: 31 AF XY: 0.0000319 AC XY: 16 AN XY: 501894

African (AFR) AF: 0.00230 AC: 50 AN: 21700

American (AMR) AF: 0.00 AC: 0 AN: 7370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12860

East Asian (EAS) AF: 0.00 AC: 0 AN: 23512

South Asian (SAS) AF: 0.00 AC: 0 AN: 22412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2764

European-Non Finnish (NFE) AF: 0.00000110 AC: 1 AN: 907674

Other (OTH) AF: 0.0000480 AC: 2 AN: 41646

GnomAD4 genome AF: 0.000536 AC: 81 AN: 151074 Hom.: 0 Cov.: 30 AF XY: 0.000569 AC XY: 42 AN XY: 73840

African (AFR) AF: 0.00184 AC: 76 AN: 41342

American (AMR) AF: 0.000132 AC: 2 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5048

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67646

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000438

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.3
DANN	Benign	0.85
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.37
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.29
Sift	Benign	0.73	T
Sift4G	Benign	0.62	T
Polyphen		0.0040	B
Vest4		0.033
MutPred		0.12		Loss of helix (P = 0.0304)
MVP		0.34
ClinPred		0.017	T
GERP RS		0.79
PromoterAI		0.018	Neutral
Varity_R		0.038
gMVP		0.27
Mutation Taster		=89/11	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: rs948561024; hg19: chr16-1203750;