chr16-1220650-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021098.3(CACNA1H):c.6718G>C(p.Ala2240Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2240T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.37

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10431567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6718G>C	p.Ala2240Pro	missense_variant	Exon 35 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.6718G>C	p.Ala2240Pro	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.6733G>C	p.Ala2245Pro	missense_variant	Exon 34 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.6703G>C	p.Ala2235Pro	missense_variant	Exon 34 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.6700G>C	p.Ala2234Pro	missense_variant	Exon 34 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.6700G>C	p.Ala2234Pro	missense_variant	Exon 35 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.6685G>C	p.Ala2229Pro	missense_variant	Exon 35 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.6679G>C	p.Ala2227Pro	missense_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.6667G>C	p.Ala2223Pro	missense_variant	Exon 34 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.6661G>C	p.Ala2221Pro	missense_variant	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000637236.3 link	n.*2637G>C		non_coding_transcript_exon_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1766G>C		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*4536G>C		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*6162G>C		non_coding_transcript_exon_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1659G>C		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1577G>C		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*2297G>C		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*1385G>C		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*1352G>C		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*632G>C		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.6718G>C		non_coding_transcript_exon_variant	Exon 35 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.6685G>C		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1834G>C		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711482.1 link	c.*197G>C		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.*197G>C		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.*197G>C		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.*632G>C		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.*632G>C		3_prime_UTR_variant	Exon 34 of 34			ENSP00000518769.1
CACNA1H	ENST00000637236.3 link	n.*2637G>C		3_prime_UTR_variant	Exon 34 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1766G>C		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*4536G>C		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*6162G>C		3_prime_UTR_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1659G>C		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1577G>C		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*2297G>C		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*1385G>C		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*1352G>C		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*632G>C		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711488.1 link	n.*1834G>C		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000621827.2 link	n.6121+597G>C		intron_variant	Intron 35 of 36	6		ENSP00000518766.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721728

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33146

American (AMR)

AF:

0.00

AC:

AN:

43416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25836

East Asian (EAS)

AF:

0.00

AC:

AN:

39346

South Asian (SAS)

AF:

0.00

AC:

AN:

85656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107794

Other (OTH)

AF:

0.00

AC:

AN:

59956

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.078

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.085

T;.;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.54

T;T;T;.

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;.;.

PhyloP100

-1.4

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.14

N;.;N;N

REVEL

Benign

0.041

Sift

Benign

0.16

T;.;T;T

Sift4G

Benign

0.15

T;.;T;T

Vest4

0.055

ClinPred

0.15

GERP RS

-3.6

Varity_R

0.085

gMVP

0.064

Mutation Taster

=95/5

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over