chr16-1202278-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021098.3(CACNA1H):​c.1828A>T​(p.Thr610Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,428,772 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T610A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.504
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12926435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1828A>T	p.Thr610Ser	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>T	p.Thr610Ser	missense_variant	Exon 9 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.1789A>T	p.Thr597Ser	missense_variant	Exon 9 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.1789A>T	p.Thr597Ser	missense_variant	Exon 9 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.1828A>T	p.Thr610Ser	missense_variant	Exon 9 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000711442.1	n.*1275A>T		non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.1828A>T		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1	n.*1275A>T		3_prime_UTR_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000640028.1	n.1385+443A>T		intron_variant	Intron 9 of 34	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1428772 Hom.: 0 Cov.: 57 AF XY: 0.00 AC XY: 0 AN XY: 707882

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 40380

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 37576

South Asian (SAS) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 59220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.22
DANN	Benign	0.59
DEOGEN2	Benign	0.064	T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.16	T;T;T;.
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Benign	0.46	N;.;N;N
PhyloP100		0.50
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.56	N;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.52	T;.;T;T
Sift4G	Benign	0.84	T;.;T;T
Polyphen		0.0010	B;.;B;B
Vest4		0.045
MutPred		0.28		Loss of glycosylation at T610 (P = 0.0495);.;Loss of glycosylation at T610 (P = 0.0495);Loss of glycosylation at T610 (P = 0.0495);
MVP		0.61
ClinPred		0.090	T
GERP RS		-4.2
Varity_R		0.044
gMVP		0.20
Mutation Taster		=97/3	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;