16-1195518-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_021098.3(CACNA1H):c.498C>T(p.Tyr166Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,604,376 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 40 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.66

Publications

3 publications found

Variant links:

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)

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 16-1195518-C-T is Benign according to our data. Variant chr16-1195518-C-T is described in ClinVar as [Benign]. Clinvar id is 460135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.66 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00479 (729/152234) while in subpopulation EAS AF = 0.0309 (160/5172). AF 95% confidence interval is 0.027. There are 10 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 729 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.459C>T	p.Tyr153Tyr	synonymous_variant	Exon 4 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.459C>T	p.Tyr153Tyr	synonymous_variant	Exon 4 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.498C>T	p.Tyr166Tyr	synonymous_variant	Exon 4 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.498C>T		non_coding_transcript_exon_variant	Exon 4 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.00480

AC:

730

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.0311

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0430

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00613

AC:

1423

AN:

232222

AF XY:

0.00597

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000914

Gnomad ASJ exome

AF:

0.00600

Gnomad EAS exome

AF:

0.0274

Gnomad FIN exome

AF:

0.0355

Gnomad NFE exome

AF:

0.000993

Gnomad OTH exome

AF:

0.00503

GnomAD4 exome

AF:

0.00230

AC:

3347

AN:

1452142

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

1631

AN XY:

721216

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33336

American (AMR)

AF:

0.0000690

AC:

AN:

43450

Ashkenazi Jewish (ASJ)

AF:

0.00733

AC:

190

AN:

25928

East Asian (EAS)

AF:

0.0210

AC:

826

AN:

39288

South Asian (SAS)

AF:

0.00136

AC:

114

AN:

83992

European-Finnish (FIN)

AF:

0.0321

AC:

1690

AN:

52646

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.000274

AC:

303

AN:

1107738

Other (OTH)

AF:

0.00363

AC:

218

AN:

60054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

193

387

580

774

967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00479

AC:

729

AN:

152234

Hom.:

Cov.:

AF XY:

0.00683

AC XY:

508

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41534

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0309

AC:

160

AN:

5172

South Asian (SAS)

AF:

0.00311

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0430

AC:

456

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000927

AC:

AN:

67996

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00137

Hom.:

Bravo

AF:

0.00189

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

8.3

(source)

DANN

Benign

0.96

PhyloP100

2.7

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over