16-1219006-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021098.3(CACNA1H):c.5924C>T(p.Ser1975Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000202 in 1,550,324 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.902

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018131495).

BP6

Variant 16-1219006-C-T is Benign according to our data. Variant chr16-1219006-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460156.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000749 (114/152298) while in subpopulation AFR AF= 0.00255 (106/41556). AF 95% confidence interval is 0.00216. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5924C>T	p.Ser1975Phe	missense_variant	Exon 34 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.5924C>T	p.Ser1975Phe	missense_variant	Exon 34 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 link	c.5906C>T	p.Ser1969Phe	missense_variant	Exon 32 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 link	c.5885C>T	p.Ser1962Phe	missense_variant	Exon 34 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 link	c.2162C>T	p.Ser721Phe	missense_variant	Exon 16 of 17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 link	c.2114C>T	p.Ser705Phe	missense_variant	Exon 17 of 18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 link	c.2096C>T	p.Ser699Phe	missense_variant	Exon 16 of 17	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000639478.1 link	n.*972C>T		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3742C>T		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000639478.1 link	n.*972C>T		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3742C>T		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491488.1	A0A1W2PQ19

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000168

AC:

AN:

154606

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

82232

show subpopulations

Gnomad AFR exome

AF:

0.00270

Gnomad AMR exome

AF:

0.0000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000672

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

199

AN:

1398026

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

689542

show subpopulations

Gnomad4 AFR exome

AF:

0.00301

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000834

Gnomad4 OTH exome

AF:

0.000190

GnomAD4 genome

AF:

0.000749

AC:

114

AN:

152298

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00255

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000579

Hom.:

Bravo

AF:

0.000922

ESP6500AA

AF:

0.00233

AC:

ESP6500EA

AF:

0.000147

AC:

ExAC

AF:

0.000185

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5924C>T (p.S1975F) alteration is located in exon 34 (coding exon 33) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 5924, causing the serine (S) at amino acid position 1975 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Apr 01, 2019

Athena Diagnostics

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

0.15

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;.;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.77

T;T;T;.

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

1.2

L;.;.;.

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.6

D;.;D;D

REVEL

Uncertain

0.35

Sift

Benign

0.11

T;.;T;T

Sift4G

Benign

0.15

T;.;T;T

Polyphen

0.68

P;.;P;P

Vest4

0.22

MVP

0.93

ClinPred

0.065

GERP RS

3.5

Varity_R

0.15

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over