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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.2631C>T	p.Asp877Asp	synonymous	Exon 12 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.2631C>T	p.Asp877Asp	synonymous	Exon 12 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.2631C>T	p.Asp877Asp	synonymous	Exon 12 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.2631C>T	p.Asp877Asp	synonymous	Exon 12 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.2631C>T	p.Asp877Asp	synonymous	Exon 12 of 34	ENSP00000518778.1	A0AAA9YHG8

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV (1)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

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;