rs371550084

Variant names:

• chr16-1220213-C-G
• rs371550084
• NM_021098.3:c.6281C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-1220213-C-G
• chr16-1220213-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_021098.3(CACNA1H):​c.6281C>G​(p.Ser2094Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,570,624 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2094L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.734
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39898896).
• BP6: Variant 16-1220213-C-G is Benign according to our data. Variant chr16-1220213-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 580824.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6281C>G	p.Ser2094Trp	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.6281C>G	p.Ser2094Trp	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.6296C>G	p.Ser2099Trp	missense_variant	Exon 34 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.6266C>G	p.Ser2089Trp	missense_variant	Exon 34 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.6263C>G	p.Ser2088Trp	missense_variant	Exon 34 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.6263C>G	p.Ser2088Trp	missense_variant	Exon 35 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.6248C>G	p.Ser2083Trp	missense_variant	Exon 35 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.6242C>G	p.Ser2081Trp	missense_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.6230C>G	p.Ser2077Trp	missense_variant	Exon 34 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.6224C>G	p.Ser2075Trp	missense_variant	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.6174C>G	p.Leu2058Leu	synonymous_variant	Exon 36 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.6123C>G	p.Leu2041Leu	synonymous_variant	Exon 35 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.6096C>G	p.Leu2032Leu	synonymous_variant	Exon 36 of 36			ENSP00000518768.1
CACNA1H	ENST00000637236.3	n.*2200C>G		non_coding_transcript_exon_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*1329C>G		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4099C>G		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5725C>G		non_coding_transcript_exon_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*1222C>G		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*1140C>G		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1860C>G		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*948C>G		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*915C>G		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.*195C>G		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.6281C>G		non_coding_transcript_exon_variant	Exon 35 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.6248C>G		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.*1397C>G		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711483.1	c.*195C>G		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.*195C>G		3_prime_UTR_variant	Exon 34 of 34			ENSP00000518769.1
CACNA1H	ENST00000637236.3	n.*2200C>G		3_prime_UTR_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*1329C>G		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4099C>G		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5725C>G		3_prime_UTR_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*1222C>G		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*1140C>G		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1860C>G		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*948C>G		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*915C>G		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.*195C>G		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711488.1	n.*1397C>G		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000621827.2	n.6121+160C>G		intron_variant	Intron 35 of 36	6		ENSP00000518766.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152192 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000193

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

GnomAD2 exomes AF: 0.0000201 AC: 4 AN: 198706 AF XY: 0.0000179

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000120 AC: 17 AN: 1418432 Hom.: 0 Cov.: 73 AF XY: 0.0000114 AC XY: 8 AN XY: 703760

African (AFR) AF: 0.000361 AC: 11 AN: 30442

American (AMR) AF: 0.00 AC: 0 AN: 40720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24326

East Asian (EAS) AF: 0.00 AC: 0 AN: 37336

South Asian (SAS) AF: 0.0000491 AC: 4 AN: 81388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44578

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5630

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095290

Other (OTH) AF: 0.00 AC: 0 AN: 58722

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152192 Hom.: 0 Cov.: 35 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

African (AFR) AF: 0.000193 AC: 8 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000426 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Mar 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6281C>G (p.S2094W) alteration is located in exon 35 (coding exon 34) of the CACNA1H gene. This alteration results from a C to G substitution at nucleotide position 6281, causing the serine (S) at amino acid position 2094 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Aug 16, 2022

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	0.13
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.83	T;T;T;.
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.5	L;.;.;.
PhyloP100		0.73
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.7	D;.;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D;.;D;D
Sift4G	Uncertain	0.017	D;.;D;D
Polyphen		0.89	P;.;D;D
Vest4		0.13
MVP		0.82
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.50
gMVP		0.19
Mutation Taster		=82/18	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: rs371550084; hg19: chr16-1270213;