16-1220681-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_021098.3(CACNA1H):c.6749G>T(p.Arg2250Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,760 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2250C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.46

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: G2P, Labcorp Genetics (formerly Invitae)

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13045707).

BP6

Variant 16-1220681-G-T is Benign according to our data. Variant chr16-1220681-G-T is described in ClinVar as Benign. ClinVar VariationId is 2117070.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6749G>T	p.Arg2250Leu	missense_variant	Exon 35 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.6749G>T	p.Arg2250Leu	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.6764G>T	p.Arg2255Leu	missense_variant	Exon 34 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.6734G>T	p.Arg2245Leu	missense_variant	Exon 34 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.6731G>T	p.Arg2244Leu	missense_variant	Exon 34 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.6731G>T	p.Arg2244Leu	missense_variant	Exon 35 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.6716G>T	p.Arg2239Leu	missense_variant	Exon 35 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.6710G>T	p.Arg2237Leu	missense_variant	Exon 35 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.6698G>T	p.Arg2233Leu	missense_variant	Exon 34 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.6692G>T	p.Arg2231Leu	missense_variant	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000637236.3 link	n.*2668G>T		non_coding_transcript_exon_variant	Exon 34 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*1797G>T		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*4567G>T		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*6193G>T		non_coding_transcript_exon_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1690G>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1608G>T		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*2328G>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*1416G>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*1383G>T		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*663G>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.6749G>T		non_coding_transcript_exon_variant	Exon 35 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.6716G>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1865G>T		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711482.1 link	c.*228G>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.*228G>T		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.*228G>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.*663G>T		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.*663G>T		3_prime_UTR_variant	Exon 34 of 34			ENSP00000518769.1
CACNA1H	ENST00000637236.3 link	n.*2668G>T		3_prime_UTR_variant	Exon 34 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*1797G>T		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*4567G>T		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*6193G>T		3_prime_UTR_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1690G>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1608G>T		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*2328G>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*1416G>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*1383G>T		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*663G>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711488.1 link	n.*1865G>T		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000621827.2 link	n.6121+628G>T		intron_variant	Intron 35 of 36	6		ENSP00000518766.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000426

AC:

AN:

234926

AF XY:

0.00000775

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457760

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33410

American (AMR)

AF:

0.00

AC:

AN:

44216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.00

AC:

AN:

86004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110732

Other (OTH)

AF:

0.00

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Aug 22, 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

0.12

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.18

T;.;.;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.83

T;T;T;.

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;.;.

PhyloP100

6.5

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.2

N;.;N;N

REVEL

Benign

0.11

Sift

Benign

0.15

T;.;T;T

Sift4G

Benign

0.64

T;.;T;T

Polyphen

0.0050

B;.;B;B

Vest4

0.39

MutPred

0.24

Loss of MoRF binding (P = 0.0469);.;.;.;

MVP

0.40

ClinPred

0.29

GERP RS

3.5

Varity_R

0.076

gMVP

0.26

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over