rs72552051

Variant names:

• chr16-1217973-A-G
• rs72552051
• NM_021098.3:c.5378A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.5378A>G​(p.Asn1793Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,605,494 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00056 (13 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.25

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0129315555).
• BP6: Variant 16-1217973-A-G is Benign according to our data. Variant chr16-1217973-A-G is described in ClinVar as [Benign]. Clinvar id is 529646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1217973-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0004 (61/152362) while in subpopulation SAS AF = 0.0116 (56/4834). AF 95% confidence interval is 0.00916. There are 1 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5378A>G	p.Asn1793Ser	missense_variant	Exon 32 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5378A>G	p.Asn1793Ser	missense_variant	Exon 32 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.5393A>G	p.Asn1798Ser	missense_variant	Exon 31 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.5396A>G	p.Asn1799Ser	missense_variant	Exon 31 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.5360A>G	p.Asn1787Ser	missense_variant	Exon 31 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.5393A>G	p.Asn1798Ser	missense_variant	Exon 32 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.5378A>G	p.Asn1793Ser	missense_variant	Exon 32 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.5339A>G	p.Asn1780Ser	missense_variant	Exon 32 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.5360A>G	p.Asn1787Ser	missense_variant	Exon 31 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.5321A>G	p.Asn1774Ser	missense_variant	Exon 31 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.5378A>G	p.Asn1793Ser	missense_variant	Exon 32 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.5360A>G	p.Asn1787Ser	missense_variant	Exon 31 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.5378A>G	p.Asn1793Ser	missense_variant	Exon 32 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.5378A>G	p.Asn1793Ser	missense_variant	Exon 32 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.5378A>G	p.Asn1793Ser	missense_variant	Exon 32 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.5378A>G		non_coding_transcript_exon_variant	Exon 32 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.*1330A>G		non_coding_transcript_exon_variant	Exon 31 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*459A>G		non_coding_transcript_exon_variant	Exon 32 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3229A>G		non_coding_transcript_exon_variant	Exon 32 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*4822A>G		non_coding_transcript_exon_variant	Exon 30 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*352A>G		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*237A>G		non_coding_transcript_exon_variant	Exon 32 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*990A>G		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*45A>G		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*45A>G		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.5360A>G		non_coding_transcript_exon_variant	Exon 31 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.5378A>G		non_coding_transcript_exon_variant	Exon 32 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.5378A>G		non_coding_transcript_exon_variant	Exon 32 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.*494A>G		non_coding_transcript_exon_variant	Exon 32 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3	n.*1330A>G		3_prime_UTR_variant	Exon 31 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*459A>G		3_prime_UTR_variant	Exon 32 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3229A>G		3_prime_UTR_variant	Exon 32 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*4822A>G		3_prime_UTR_variant	Exon 30 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*352A>G		3_prime_UTR_variant	Exon 33 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*237A>G		3_prime_UTR_variant	Exon 32 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*990A>G		3_prime_UTR_variant	Exon 33 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*45A>G		3_prime_UTR_variant	Exon 33 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*45A>G		3_prime_UTR_variant	Exon 33 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1	n.*494A>G		3_prime_UTR_variant	Exon 32 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152244 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00119 AC: 278 AN: 234342 AF XY: 0.00168

Gnomad AFR exome AF: 0.0000722

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: 0.00

Gnomad OTH exome AF: 0.000698

GnomAD4 exome AF: 0.000555 AC: 807 AN: 1453132 Hom.: 13 Cov.: 31 AF XY: 0.000859 AC XY: 620 AN XY: 722082

African (AFR) AF: 0.0000600 AC: 2 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 43956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39308

South Asian (SAS) AF: 0.00914 AC: 773 AN: 84608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51462

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1108722

Other (OTH) AF: 0.000383 AC: 23 AN: 60064

GnomAD4 genome AF: 0.000400 AC: 61 AN: 152362 Hom.: 1 Cov.: 34 AF XY: 0.000604 AC XY: 45 AN XY: 74510

African (AFR) AF: 0.0000962 AC: 4 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000502 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.00133 AC: 160

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 19, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	0.34
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;.
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.8	L;.;.;.
PhyloP100		7.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.9	D;.;D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.076	T;.;T;T
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.80
MVP		0.95
ClinPred		0.099	T
GERP RS		3.5
Varity_R		0.48
gMVP		0.81
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

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Other links and lift over

dbSNP: rs72552051; hg19: chr16-1267973;