rs201449513

Variant names:

• chr16-1202278-A-G
• rs201449513
• NM_021098.3:c.1828A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-1202278-A-G
• chr16-1202278-A-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.1828A>G​(p.Thr610Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000759 in 1,581,092 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.504
• 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01181522).
• BP6: Variant 16-1202278-A-G is Benign according to our data. Variant chr16-1202278-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 460053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000144 (22/152320) while in subpopulation EAS AF = 0.00406 (21/5178). AF 95% confidence interval is 0.00272. There are 1 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.1789A>G	p.Thr597Ala	missense_variant	Exon 9 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.1789A>G	p.Thr597Ala	missense_variant	Exon 9 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.1828A>G	p.Thr610Ala	missense_variant	Exon 9 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000711442.1	n.*1275A>G		non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.1828A>G		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1	n.*1275A>G		3_prime_UTR_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000640028.1	n.1385+443A>G		intron_variant	Intron 9 of 34	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152202 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000126 AC: 24 AN: 190914 AF XY: 0.0000955

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000340

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000198

GnomAD4 exome AF: 0.0000686 AC: 98 AN: 1428772 Hom.: 0 Cov.: 57 AF XY: 0.0000622 AC XY: 44 AN XY: 707882

African (AFR) AF: 0.00 AC: 0 AN: 32632

American (AMR) AF: 0.0000248 AC: 1 AN: 40380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25504

East Asian (EAS) AF: 0.00192 AC: 72 AN: 37576

South Asian (SAS) AF: 0.000111 AC: 9 AN: 81334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1097740

Other (OTH) AF: 0.000236 AC: 14 AN: 59220

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152320 Hom.: 1 Cov.: 34 AF XY: 0.000148 AC XY: 11 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.0000942 AC: 11

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Jul 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.13
DANN	Benign	0.43
DEOGEN2	Benign	0.077	T;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.15	T;T;T;.
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.36	N;.;N;N
PhyloP100		0.50
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.13	N;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.50	T;.;T;T
Sift4G	Benign	0.91	T;.;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.018
MVP		0.56
ClinPred		0.019	T
GERP RS		-4.2
Varity_R		0.039
gMVP		0.22
Mutation Taster		=98/2	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: rs201449513; hg19: chr16-1252278;