16-1211727-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_021098.3(CACNA1H):c.4488G>A(p.Ser1496Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,612,452 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 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.414

Publications

0 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 16-1211727-G-A is Benign according to our data. Variant chr16-1211727-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96012.

BP7

Synonymous conserved (PhyloP=-0.414 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000276 (42/152222) while in subpopulation NFE AF = 0.000514 (35/68028). AF 95% confidence interval is 0.000379. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 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.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4524G>A	p.Ser1508Ser	synonymous_variant	Exon 24 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4449G>A	p.Ser1483Ser	synonymous_variant	Exon 24 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4449G>A	p.Ser1483Ser	synonymous_variant	Exon 24 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4488G>A	p.Ser1496Ser	synonymous_variant	Exon 24 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*458G>A		non_coding_transcript_exon_variant	Exon 24 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2401G>A		non_coding_transcript_exon_variant	Exon 24 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3935G>A		non_coding_transcript_exon_variant	Exon 23 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4488G>A		non_coding_transcript_exon_variant	Exon 24 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*458G>A		3_prime_UTR_variant	Exon 24 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2401G>A		3_prime_UTR_variant	Exon 24 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3935G>A		3_prime_UTR_variant	Exon 23 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.000514

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000177

AC:

AN:

248224

AF XY:

0.000141

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000330

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.000488

AC:

712

AN:

1460230

Hom.:

Cov.:

AF XY:

0.000447

AC XY:

325

AN XY:

726406

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000583

AC:

648

AN:

1111684

Other (OTH)

AF:

0.000961

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000276

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000514

AC:

AN:

68028

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000253

Hom.:

Bravo

AF:

0.000238

EpiCase

AF:

0.000709

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BP4, BP7 -

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

Benign:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

-0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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