16-1219055-C-T

Variant names:

• chr16-1219055-C-T
• rs753397534
• NM_021098.3:c.5973C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_021098.3(CACNA1H):​c.5973C>T​(p.Ser1991Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,549,588 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000021 (1 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.03
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 16-1219055-C-T is Benign according to our data. Variant chr16-1219055-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1085467.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5973C>T	p.Ser1991Ser	synonymous_variant	Exon 34 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5973C>T	p.Ser1991Ser	synonymous_variant	Exon 34 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.5988C>T	p.Ser1996Ser	synonymous_variant	Exon 33 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.5958C>T	p.Ser1986Ser	synonymous_variant	Exon 33 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.5955C>T	p.Ser1985Ser	synonymous_variant	Exon 33 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.5955C>T	p.Ser1985Ser	synonymous_variant	Exon 34 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.5940C>T	p.Ser1980Ser	synonymous_variant	Exon 34 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.5934C>T	p.Ser1978Ser	synonymous_variant	Exon 34 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.5922C>T	p.Ser1974Ser	synonymous_variant	Exon 33 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.5916C>T	p.Ser1972Ser	synonymous_variant	Exon 33 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.5973C>T	p.Ser1991Ser	synonymous_variant	Exon 34 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.5922C>T	p.Ser1974Ser	synonymous_variant	Exon 33 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.5895C>T	p.Ser1965Ser	synonymous_variant	Exon 34 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.5973C>T	p.Ser1991Ser	synonymous_variant	Exon 34 of 35			ENSP00000518772.1
CACNA1H	ENST00000621827.2	n.5973C>T		non_coding_transcript_exon_variant	Exon 34 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.*1892C>T		non_coding_transcript_exon_variant	Exon 33 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*1021C>T		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3791C>T		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5417C>T		non_coding_transcript_exon_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*914C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*832C>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1552C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*640C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*607C>T		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.5922C>T		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.5973C>T		non_coding_transcript_exon_variant	Exon 34 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.5940C>T		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.*1089C>T		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3	n.*1892C>T		3_prime_UTR_variant	Exon 33 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*1021C>T		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3791C>T		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5417C>T		3_prime_UTR_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*914C>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*832C>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1552C>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*640C>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*607C>T		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1	n.*1089C>T		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000711456.1	c.5887+404C>T		intron_variant	Intron 33 of 33			ENSP00000518769.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 151656 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.0000208 AC: 29 AN: 1397386 Hom.: 1 Cov.: 34 AF XY: 0.0000174 AC XY: 12 AN XY: 689254

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000232 AC: 25 AN: 1078622

Other (OTH) AF: 0.0000173 AC: 1 AN: 57952

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Aug 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.1
DANN	Benign	0.71
PhyloP100		1.0

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

Other links and lift over

dbSNP: rs753397534; hg19: chr16-1269055; COSMIC: COSV52356630; COSMIC: COSV52356630;