rs2745167

Variant names:

• chr16-1205545-T-C
• rs2745167
• NM_021098.3:c.2603+280T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021098.3(CACNA1H):​c.2603+280T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 152,150 control chromosomes in the GnomAD database, including 14,692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.42 (14692 hom., cov: 34)
• Consequence: CACNA1H NM_021098.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.196
• Publications: 10 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)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-1205545-T-C is Benign according to our data. Variant chr16-1205545-T-C is described in ClinVar as Benign. ClinVar VariationId is 1296140.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2603+280T>C		intron_variant	Intron 11 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2603+280T>C		intron_variant	Intron 11 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.2603+280T>C		intron_variant	Intron 11 of 33	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.2603+280T>C		intron_variant	Intron 11 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.2603+280T>C		intron_variant	Intron 11 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.2603+280T>C		intron_variant	Intron 11 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.2603+280T>C		intron_variant	Intron 11 of 34	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.2564+280T>C		intron_variant	Intron 11 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.2603+280T>C		intron_variant	Intron 11 of 33	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.2564+280T>C		intron_variant	Intron 11 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.2603+280T>C		intron_variant	Intron 11 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.2603+280T>C		intron_variant	Intron 11 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.2603+280T>C		intron_variant	Intron 11 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.2603+280T>C		intron_variant	Intron 11 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.2603+280T>C		intron_variant	Intron 11 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.2603+280T>C		intron_variant	Intron 11 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.2603+280T>C		intron_variant	Intron 11 of 33	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.2603+280T>C		intron_variant	Intron 11 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*516+280T>C		intron_variant	Intron 11 of 34	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*2050+280T>C		intron_variant	Intron 10 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.2603+280T>C		intron_variant	Intron 11 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.2603+280T>C		intron_variant	Intron 11 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.2603+280T>C		intron_variant	Intron 11 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.2603+280T>C		intron_variant	Intron 11 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.2603+280T>C		intron_variant	Intron 11 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.2603+280T>C		intron_variant	Intron 11 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.2603+280T>C		intron_variant	Intron 11 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.2603+280T>C		intron_variant	Intron 11 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.2603+280T>C		intron_variant	Intron 11 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64455 AN: 152032 Hom.: 14667 Cov.: 34

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.0702

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.392

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.424 AC: 64520 AN: 152150 Hom.: 14692 Cov.: 34 AF XY: 0.419 AC XY: 31182 AN XY: 74394

African (AFR) AF: 0.370 AC: 15335 AN: 41496

American (AMR) AF: 0.321 AC: 4908 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1017 AN: 3470

East Asian (EAS) AF: 0.0698 AC: 362 AN: 5184

South Asian (SAS) AF: 0.351 AC: 1691 AN: 4820

European-Finnish (FIN) AF: 0.524 AC: 5553 AN: 10596

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.504 AC: 34245 AN: 67974

Other (OTH) AF: 0.386 AC: 816 AN: 2112

Alfa AF: 0.472 Hom.: 25283

Bravo AF: 0.405

Asia WGS AF: 0.219 AC: 765 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.8
DANN	Benign	0.63
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs2745167; hg19: chr16-1255545;