rs538538654

Positions:

• chr16-1220497-C-A
• chr16-1220497-C-G
• chr16-1220497-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_021098.3(CACNA1H):​c.6565C>A​(p.Pro2189Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,542,930 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000093 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.36

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6565C>A	p.Pro2189Thr	missense_variant	35/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6565C>A	p.Pro2189Thr	missense_variant	35/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.6547C>A	p.Pro2183Thr	missense_variant	33/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.6526C>A	p.Pro2176Thr	missense_variant	35/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2803C>A	p.Pro935Thr	missense_variant	17/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2755C>A	p.Pro919Thr	missense_variant	18/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2737C>A	p.Pro913Thr	missense_variant	17/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1613C>A		non_coding_transcript_exon_variant	35/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4383C>A		non_coding_transcript_exon_variant	35/35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*1613C>A		3_prime_UTR_variant	35/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4383C>A		3_prime_UTR_variant	35/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000412 AC: 7 AN: 169952 Hom.: 0 AF XY: 0.0000430 AC XY: 4 AN XY: 92984

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000667

Gnomad SAS exome AF: 0.0000611

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000935 AC: 13 AN: 1390882 Hom.: 0 Cov.: 35 AF XY: 0.0000116 AC XY: 8 AN XY: 687628

Gnomad4 AFR exome AF: 0.000197

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000136

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000369

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74252

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ExAC AF: 0.0000598 AC: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D;D;D;.
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.0	M;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D;.;D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.011	D;.;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.32
MVP		0.69
ClinPred		0.93	D
GERP RS		4.7
Varity_R		0.88
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs538538654; hg19: chr16-1270497;