chr16-1220166-C-G

Variant names:

• chr16-1220166-C-G
• rs59844753
• NM_021098.3:c.6234C>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_021098.3(CACNA1H):​c.6234C>G​(p.Cys2078Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000197 in 1,520,050 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: 𝑓 0.0000066 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.72

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25535327).
• BP6: Variant 16-1220166-C-G is Benign according to our data. Variant chr16-1220166-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2951985.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6234C>G	p.Cys2078Trp	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.6234C>G	p.Cys2078Trp	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.6216C>G	p.Cys2072Trp	missense_variant	Exon 33 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.6195C>G	p.Cys2065Trp	missense_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2472C>G	p.Cys824Trp	missense_variant	Exon 17 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2424C>G	p.Cys808Trp	missense_variant	Exon 18 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2406C>G	p.Cys802Trp	missense_variant	Exon 17 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1282C>G		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4052C>G		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*1282C>G		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4052C>G		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1367836 Hom.: 0 Cov.: 72 AF XY: 0.00000149 AC XY: 1 AN XY: 673212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000622

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

May 10, 2024

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

May 21, 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	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.73	T;T;T;.
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N;.;N;N
REVEL	Benign	0.091
Sift	Benign	0.13	T;.;T;T
Sift4G	Benign	0.19	T;.;T;T
Polyphen		0.98	D;.;D;D
Vest4		0.39
MutPred		0.24		Gain of MoRF binding (P = 0.043);.;.;.;
MVP		0.85
ClinPred		0.56	D
GERP RS		-0.98
Varity_R		0.13
gMVP		0.26

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: rs59844753; hg19: chr16-1270166;