rs61056448

Variant names:

• chr16-1202152-G-A
• rs61056448
• NM_021098.3:c.1702G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1202152-G-A
• chr16-1202152-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.1702G>A​(p.Asp568Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,550,318 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. D568V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 1.30
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00608176).
• BP6: Variant 16-1202152-G-A is Benign according to our data. Variant chr16-1202152-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00101 (154/152366) while in subpopulation SAS AF = 0.00455 (22/4832). AF 95% confidence interval is 0.00308. There are 1 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 154 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.1702G>A	p.Asp568Asn	missense	Exon 9 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.1702G>A	p.Asp568Asn	missense	Exon 9 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.1702G>A	p.Asp568Asn	missense	Exon 9 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.1702G>A	p.Asp568Asn	missense	Exon 9 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.1702G>A	p.Asp568Asn	missense	Exon 9 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.000998 AC: 152 AN: 152248 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00194 AC: 283 AN: 146046 AF XY: 0.00227

Gnomad AFR exome AF: 0.000149

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.0000929

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.00113 AC: 1574 AN: 1397952 Hom.: 19 Cov.: 36 AF XY: 0.00126 AC XY: 867 AN XY: 689642

African (AFR) AF: 0.000475 AC: 15 AN: 31590

American (AMR) AF: 0.00139 AC: 50 AN: 35848

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 366 AN: 25190

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35748

South Asian (SAS) AF: 0.00298 AC: 236 AN: 79302

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47262

Middle Eastern (MID) AF: 0.0121 AC: 69 AN: 5692

European-Non Finnish (NFE) AF: 0.000646 AC: 697 AN: 1079342

Other (OTH) AF: 0.00240 AC: 139 AN: 57978

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152366 Hom.: 1 Cov.: 34 AF XY: 0.00105 AC XY: 78 AN XY: 74506

African (AFR) AF: 0.000144 AC: 6 AN: 41590

American (AMR) AF: 0.000849 AC: 13 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

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

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00218 Hom.: 1

Bravo AF: 0.00114

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000593 AC: 4

ExAC AF: 0.00103 AC: 102

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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)
-	-	-	Epilepsy, childhood absence, susceptibility to, 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0061	T
MetaSVM	Uncertain	-0.094	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.15
Sift	Benign	0.44	T
Sift4G	Benign	0.49	T
Polyphen		0.0040	B
Vest4		0.27
MVP		0.63
ClinPred		0.0021	T
GERP RS		2.9
Varity_R		0.063
gMVP		0.39
Mutation Taster		=99/1	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: rs61056448; hg19: chr16-1252152; COSMIC: COSV62005400; COSMIC: COSV62005400;