dbSNP rs747200195: CACNA1H:p.Asp1248Glu (chr16-1209412-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021098.3(CACNA1H):c.3744C>G(p.Asp1248Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. D1248N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense, splice_region

Scores

Splicing: ADA: 0.00002241

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.547

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1354649).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 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.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 17 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 link	c.3744C>G	p.Asp1248Glu	missense_variant, splice_region_variant	Exon 16 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 link	c.3705C>G	p.Asp1235Glu	missense_variant, splice_region_variant	Exon 17 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000637236.2 link	n.57C>G		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3744C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1657C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000640028.1 link	n.*1657C>G		3_prime_UTR_variant	Exon 17 of 35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1444546

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718984

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

0.0087

BayesDel_noAF

Benign

-0.23

CADD

Benign

5.2

DANN

Benign

0.94

DEOGEN2

Benign

0.091

T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.71

T;T;T;.

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.5

L;.;L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.23

N;.;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.61

T;.;T;T

Sift4G

Benign

1.0

T;.;T;T

Polyphen

1.0

D;.;P;P

Vest4

0.44

MutPred

0.33

Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.86

ClinPred

0.16

GERP RS

-5.8

Varity_R

0.040

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.18

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over