16-1215283-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_021098.3(CACNA1H):c.5081T>C(p.Met1694Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,608,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1694V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.74

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 -4 ACMG points.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5081T>C	p.Met1694Thr	missense_variant	Exon 29 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.5081T>C	p.Met1694Thr	missense_variant	Exon 29 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5096T>C	p.Met1699Thr	missense_variant	Exon 28 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5099T>C	p.Met1700Thr	missense_variant	Exon 28 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5063T>C	p.Met1688Thr	missense_variant	Exon 28 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5096T>C	p.Met1699Thr	missense_variant	Exon 29 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5081T>C	p.Met1694Thr	missense_variant	Exon 29 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5042T>C	p.Met1681Thr	missense_variant	Exon 29 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5063T>C	p.Met1688Thr	missense_variant	Exon 28 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5024T>C	p.Met1675Thr	missense_variant	Exon 28 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5081T>C	p.Met1694Thr	missense_variant	Exon 29 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5063T>C	p.Met1688Thr	missense_variant	Exon 28 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5081T>C	p.Met1694Thr	missense_variant	Exon 29 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5081T>C	p.Met1694Thr	missense_variant	Exon 29 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5081T>C	p.Met1694Thr	missense_variant	Exon 29 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5081T>C		non_coding_transcript_exon_variant	Exon 29 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1033T>C		non_coding_transcript_exon_variant	Exon 28 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*162T>C		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2932T>C		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4525T>C		non_coding_transcript_exon_variant	Exon 27 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.5063T>C		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.5063T>C		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*82T>C		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.5081T>C		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.5081T>C		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5063T>C		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5081T>C		non_coding_transcript_exon_variant	Exon 29 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5081T>C		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*82T>C		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1033T>C		3_prime_UTR_variant	Exon 28 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*162T>C		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2932T>C		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4525T>C		3_prime_UTR_variant	Exon 27 of 34			ENSP00000518758.1
CACNA1H	ENST00000711451.1 link	n.*82T>C		3_prime_UTR_variant	Exon 29 of 36			ENSP00000518763.1
CACNA1H	ENST00000711488.1 link	n.*82T>C		3_prime_UTR_variant	Exon 28 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000417

AC:

AN:

239896

AF XY:

0.00000767

show subpopulations

Gnomad AFR exome

AF:

0.000139

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:

0.0000737

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000226

AC:

329

AN:

1456420

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

161

AN XY:

724014

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

44196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.00

AC:

AN:

85164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000290

AC:

322

AN:

1110064

Other (OTH)

AF:

0.0000830

AC:

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41582

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Uncertain:1

Jan 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 18, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5081T>C (p.M1694T) alteration is located in exon 29 (coding exon 28) of the CACNA1H gene. This alteration results from a T to C substitution at nucleotide position 5081, causing the methionine (M) at amino acid position 1694 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

May 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 529593). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. This variant is present in population databases (rs375015931, gnomAD 0.009%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1694 of the CACNA1H protein (p.Met1694Thr). -

not provided

Uncertain:1

Oct 30, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.76

D;.;.;.

Eigen

Benign

0.089

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D;D;.

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

0.68

N;.;.;.

PhyloP100

7.7

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.5

D;.;D;D

REVEL

Pathogenic

0.66

Sift

Benign

0.041

D;.;D;D

Sift4G

Uncertain

0.011

D;.;D;D

Polyphen

0.88

P;.;P;P

Vest4

0.75

MVP

0.92

ClinPred

0.23

GERP RS

4.0

Varity_R

0.46

gMVP

0.68

Mutation Taster

=21/79

disease causing

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over