16-1206131-C-T

Variant names:

• chr16-1206131-C-T
• rs59636120
• NM_021098.3:c.2631C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):​c.2631C>T​(p.Asp877Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,585,060 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (9 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.91
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 16-1206131-C-T is Benign according to our data. Variant chr16-1206131-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00609 (928/152340) while in subpopulation AFR AF = 0.0201 (834/41570). AF 95% confidence interval is 0.0189. There are 10 homozygotes in GnomAd4. There are 441 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 928 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.2592C>T	p.Asp864Asp	synonymous_variant	Exon 12 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.2592C>T	p.Asp864Asp	synonymous_variant	Exon 12 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.2631C>T	p.Asp877Asp	synonymous_variant	Exon 12 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*544C>T		non_coding_transcript_exon_variant	Exon 12 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*2078C>T		non_coding_transcript_exon_variant	Exon 11 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.2631C>T		non_coding_transcript_exon_variant	Exon 12 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1	n.*544C>T		3_prime_UTR_variant	Exon 12 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*2078C>T		3_prime_UTR_variant	Exon 11 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 927 AN: 152222 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00184 AC: 374 AN: 203608 AF XY: 0.00152

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.000359

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00618

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.000864 AC: 1238 AN: 1432720 Hom.: 9 Cov.: 31 AF XY: 0.000791 AC XY: 562 AN XY: 710440

African (AFR) AF: 0.0198 AC: 651 AN: 32924

American (AMR) AF: 0.000409 AC: 17 AN: 41550

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25568

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38210

South Asian (SAS) AF: 0.0000368 AC: 3 AN: 81630

European-Finnish (FIN) AF: 0.00625 AC: 298 AN: 47692

Middle Eastern (MID) AF: 0.00111 AC: 6 AN: 5386

European-Non Finnish (NFE) AF: 0.000141 AC: 155 AN: 1100432

Other (OTH) AF: 0.00179 AC: 106 AN: 59328

GnomAD4 genome AF: 0.00609 AC: 928 AN: 152340 Hom.: 10 Cov.: 33 AF XY: 0.00592 AC XY: 441 AN XY: 74488

African (AFR) AF: 0.0201 AC: 834 AN: 41570

American (AMR) AF: 0.000784 AC: 12 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68030

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00176 Hom.: 2

Bravo AF: 0.00615

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 15, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Jul 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 02, 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
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.0
DANN	Benign	0.81
PhyloP100		-1.9
Mutation Taster		=98/2	polymorphism

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: rs59636120; hg19: chr16-1256131; COSMIC: COSV61990077; COSMIC: COSV61990077;