dbSNP rs757467258: CACNA1H:c.4039-8C>G (chr16-1210779-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021098.3(CACNA1H):c.4039-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 splice_region, intron

Scores

Splicing: ADA: 0.00007024

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.320

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: 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 (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4039-8C>G		splice_region_variant, intron_variant	Intron 20 of 34	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 34	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 33	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 33			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 34	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4000-8C>G	splice_region_variant, intron_variant	Intron 20 of 34	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 33	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4000-8C>G	splice_region_variant, intron_variant	Intron 20 of 33			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 33			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 36	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*9-8C>G	splice_region_variant, intron_variant	Intron 20 of 33	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 34	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1952-8C>G	splice_region_variant, intron_variant	Intron 20 of 34	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3486-8C>G	splice_region_variant, intron_variant	Intron 19 of 33			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 36			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 35			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4039-8C>G	splice_region_variant, intron_variant	Intron 20 of 34			ENSP00000518777.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111396

Other (OTH)

AF:

0.00

AC:

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.74

(source)

DANN

Benign

0.40

PhyloP100

-0.32

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000070

dbscSNV1_RF

Benign

0.088

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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rs757467258

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over