rs368976749

Variant names:

• chr16-1202294-C-T
• rs368976749
• NM_021098.3:c.1844C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1202294-C-T
• chr16-1202294-C-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.1844C>T​(p.Thr615Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00055 in 1,584,866 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T615R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00057 (3 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.52
• 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29840767).
• BP6: Variant 16-1202294-C-T is Benign according to our data. Variant chr16-1202294-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96004.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000368 (56/152346) while in subpopulation AMR AF = 0.000653 (10/15306). AF 95% confidence interval is 0.000431. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 56 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.1844C>T	p.Thr615Met	missense	Exon 9 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.1844C>T	p.Thr615Met	missense	Exon 9 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.1844C>T	p.Thr615Met	missense	Exon 9 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.1844C>T	p.Thr615Met	missense	Exon 9 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.1844C>T	p.Thr615Met	missense	Exon 9 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152228 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000414 AC: 81 AN: 195798 AF XY: 0.000400

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000402

Gnomad ASJ exome AF: 0.000333

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000725

Gnomad OTH exome AF: 0.000586

GnomAD4 exome AF: 0.000570 AC: 816 AN: 1432520 Hom.: 3 Cov.: 57 AF XY: 0.000559 AC XY: 397 AN XY: 710038

African (AFR) AF: 0.0000610 AC: 2 AN: 32770

American (AMR) AF: 0.000390 AC: 16 AN: 40974

Ashkenazi Jewish (ASJ) AF: 0.000117 AC: 3 AN: 25546

East Asian (EAS) AF: 0.00 AC: 0 AN: 37898

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81754

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48788

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5740

European-Non Finnish (NFE) AF: 0.000693 AC: 762 AN: 1099698

Other (OTH) AF: 0.000489 AC: 29 AN: 59352

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152346 Hom.: 0 Cov.: 34 AF XY: 0.000349 AC XY: 26 AN XY: 74494

African (AFR) AF: 0.0000962 AC: 4 AN: 41588

American (AMR) AF: 0.000653 AC: 10 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68024

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

Alfa AF: 0.000403 Hom.: 0

Bravo AF: 0.000434

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000124 AC: 1

ExAC AF: 0.000376 AC: 44

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	CACNA1H-related disorder (1)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.66
MVP		0.91
ClinPred		0.29	T
GERP RS		4.1
Varity_R		0.27
gMVP		0.62
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs368976749; hg19: chr16-1252294; COSMIC: COSV108192880; COSMIC: COSV108192880;