rs200520956

Variant names:

• chr16-1200261-A-C
• rs200520956
• NM_021098.3:c.809A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.809A>C​(p.Asn270Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,596,506 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).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.15
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060691893).
• BP6: Variant 16-1200261-A-C is Benign according to our data. Variant chr16-1200261-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460189.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000342 (52/152258) while in subpopulation NFE AF = 0.000544 (37/68000). AF 95% confidence interval is 0.000405. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.770A>C	p.Asn257Thr	missense_variant	Exon 7 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.770A>C	p.Asn257Thr	missense_variant	Exon 7 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.809A>C	p.Asn270Thr	missense_variant	Exon 7 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*256A>C		non_coding_transcript_exon_variant	Exon 6 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.809A>C		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1	n.*256A>C		3_prime_UTR_variant	Exon 6 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000544

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000346 AC: 80 AN: 231174 AF XY: 0.000372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000145

Gnomad NFE exome AF: 0.000683

Gnomad OTH exome AF: 0.000352

GnomAD4 exome AF: 0.000630 AC: 910 AN: 1444248 Hom.: 0 Cov.: 31 AF XY: 0.000592 AC XY: 424 AN XY: 716050

African (AFR) AF: 0.000152 AC: 5 AN: 32928

American (AMR) AF: 0.000140 AC: 6 AN: 42812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25606

East Asian (EAS) AF: 0.00 AC: 0 AN: 39168

South Asian (SAS) AF: 0.00 AC: 0 AN: 83986

European-Finnish (FIN) AF: 0.000194 AC: 10 AN: 51446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.000782 AC: 863 AN: 1102944

Other (OTH) AF: 0.000436 AC: 26 AN: 59644

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74442

African (AFR) AF: 0.000217 AC: 9 AN: 41558

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000514 Hom.: 1

Bravo AF: 0.000363

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000475 AC: 4

ExAC AF: 0.000432 AC: 52

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CACNA1H-related disorder Uncertain:1

Apr 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CACNA1H c.809A>C variant is predicted to result in the amino acid substitution p.Asn270Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.068% of alleles in individuals of European (Non-Finnish) descent in gnomAD (https://gnomad.broadinstitute.org/variant/chr16-1250261-A-C). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Uncertain:1

Jun 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.809A>C (p.N270T) alteration is located in exon 7 (coding exon 6) of the CACNA1H gene. This alteration results from a A to C substitution at nucleotide position 809, causing the asparagine (N) at amino acid position 270 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.60
DEOGEN2	Benign	0.38	T;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T;T;T;.
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.061	T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.70	N;.;N;N
PhyloP100		3.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.34	N;.;N;N
REVEL	Benign	0.22
Sift	Benign	0.70	T;.;T;T
Sift4G	Benign	0.58	T;.;T;T
Polyphen		0.47	P;.;B;B
Vest4		0.41
MVP		0.84
ClinPred		0.021	T
GERP RS		0.88
Varity_R		0.045
gMVP		0.76
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200520956; hg19: chr16-1250261; COSMIC: COSV62000394; COSMIC: COSV62000394;