16-1220701-C-T

Variant names:

• chr16-1220701-C-T
• rs770202267
• NM_021098.3:c.6769C>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_021098.3(CACNA1H):​c.6769C>T​(p.Arg2257Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,459,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.53

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22416091).
• BP6: Variant 16-1220701-C-T is Benign according to our data. Variant chr16-1220701-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529618.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6769C>T	p.Arg2257Trp	missense_variant	Exon 35 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6769C>T	p.Arg2257Trp	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.6751C>T	p.Arg2251Trp	missense_variant	Exon 33 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.6730C>T	p.Arg2244Trp	missense_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.3007C>T	p.Arg1003Trp	missense_variant	Exon 17 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2959C>T	p.Arg987Trp	missense_variant	Exon 18 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2941C>T	p.Arg981Trp	missense_variant	Exon 17 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1817C>T		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4587C>T		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*1817C>T		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4587C>T		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000208 AC: 5 AN: 240636 Hom.: 0 AF XY: 0.0000228 AC XY: 3 AN XY: 131734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000570

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459402 Hom.: 0 Cov.: 35 AF XY: 0.00000689 AC XY: 5 AN XY: 725972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Mar 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.82	T;T;T;.
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.97	L;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;.;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.059	T;.;T;T
Sift4G	Uncertain	0.012	D;.;D;D
Polyphen		0.013	B;.;B;B
Vest4		0.27
MutPred		0.38		Loss of solvent accessibility (P = 0.001);.;.;.;
MVP		0.81
ClinPred		0.62	D
GERP RS		1.1
Varity_R		0.13
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs770202267; hg19: chr16-1270701;