dbSNP rs60938322: CACNA1H:p.Phe1662Phe (chr16-1215028-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_021098.3(CACNA1H):c.4986C>T(p.Phe1662Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,612,978 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00038 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 3 hom. )

Consequence

CACNA1H
NM_021098.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -3.59

Publications

1 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: Labcorp Genetics (formerly Invitae), G2P
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 16-1215028-C-T is Benign according to our data. Variant chr16-1215028-C-T is described in ClinVar as Benign. ClinVar VariationId is 529621.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-3.59 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000301 (439/1460702) while in subpopulation MID AF = 0.00121 (7/5766). AF 95% confidence interval is 0.000569. There are 3 homozygotes in GnomAdExome4. There are 228 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 58 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.4986C>T	p.Phe1662Phe	synonymous	Exon 28 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.4968C>T	p.Phe1656Phe	synonymous	Exon 27 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.4986C>T	p.Phe1662Phe	synonymous	Exon 28 of 35	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6	TSL:1	c.5001C>T	p.Phe1667Phe	synonymous	Exon 27 of 34	ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1		c.5004C>T	p.Phe1668Phe	synonymous	Exon 27 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00923

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000551

AC:

136

AN:

246738

AF XY:

0.000581

show subpopulations

Gnomad AFR exome

AF:

0.000133

Gnomad AMR exome

AF:

0.000466

Gnomad ASJ exome

AF:

0.00824

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000242

Gnomad OTH exome

AF:

0.000500

GnomAD4 exome

AF:

0.000301

AC:

439

AN:

1460702

Hom.:

Cov.:

AF XY:

0.000314

AC XY:

228

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33464

American (AMR)

AF:

0.000403

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.00798

AC:

208

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000697

AC:

AN:

86068

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53182

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000126

AC:

140

AN:

1111496

Other (OTH)

AF:

0.000895

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000381

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41564

American (AMR)

AF:

0.000327

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00923

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68020

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000965

Hom.:

Bravo

AF:

0.000434

EpiCase

AF:

0.000763

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

CACNA1H-related disorder (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

3.4

(source)

DANN

Benign

0.95

PhyloP100

-3.6

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over