16-1202369-C-T

Variant names:

• chr16-1202369-C-T
• rs61734410
• NM_021098.3:c.1919C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021098.3(CACNA1H):​c.1919C>T​(p.Pro640Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,557,154 control chromosomes in the GnomAD database, including 78,216 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P640A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.31 (8504 hom., cov: 34)
  • Exomes 𝑓: 0.29 (69712 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.07
• Publications: 40 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2459473E-6).
• BP6: Variant 16-1202369-C-T is Benign according to our data. Variant chr16-1202369-C-T is described in ClinVar as Benign. ClinVar VariationId is 96005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

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.1919C>T	p.Pro640Leu	missense	Exon 9 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.1919C>T	p.Pro640Leu	missense	Exon 9 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.1919C>T	p.Pro640Leu	missense	Exon 9 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.1919C>T	p.Pro640Leu	missense	Exon 9 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.1919C>T	p.Pro640Leu	missense	Exon 9 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47057 AN: 152030 Hom.: 8495 Cov.: 34

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.314

GnomAD2 exomes AF: 0.386 AC: 61080 AN: 158394 AF XY: 0.376

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.578

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.815

Gnomad FIN exome AF: 0.316

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.295 AC: 414325 AN: 1405006 Hom.: 69712 Cov.: 60 AF XY: 0.297 AC XY: 206151 AN XY: 693994

African (AFR) AF: 0.232 AC: 7418 AN: 32012

American (AMR) AF: 0.557 AC: 20466 AN: 36752

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 9175 AN: 25120

East Asian (EAS) AF: 0.845 AC: 30628 AN: 36228

South Asian (SAS) AF: 0.385 AC: 30603 AN: 79444

European-Finnish (FIN) AF: 0.325 AC: 15181 AN: 46696

Middle Eastern (MID) AF: 0.301 AC: 1715 AN: 5704

European-Non Finnish (NFE) AF: 0.259 AC: 280682 AN: 1084742

Other (OTH) AF: 0.317 AC: 18457 AN: 58308

GnomAD4 genome AF: 0.309 AC: 47086 AN: 152148 Hom.: 8504 Cov.: 34 AF XY: 0.319 AC XY: 23701 AN XY: 74412

African (AFR) AF: 0.232 AC: 9635 AN: 41518

American (AMR) AF: 0.461 AC: 7047 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1261 AN: 3472

East Asian (EAS) AF: 0.820 AC: 4242 AN: 5172

South Asian (SAS) AF: 0.420 AC: 2025 AN: 4824

European-Finnish (FIN) AF: 0.325 AC: 3450 AN: 10612

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18389 AN: 67948

Other (OTH) AF: 0.315 AC: 664 AN: 2108

Alfa AF: 0.290 Hom.: 6225

Bravo AF: 0.317

TwinsUK AF: 0.249 AC: 923

ALSPAC AF: 0.261 AC: 1004

ESP6500AA AF: 0.194 AC: 747

ESP6500EA AF: 0.238 AC: 1905

ExAC AF: 0.296 AC: 31438

Asia WGS AF: 0.551 AC: 1913 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Epilepsy, childhood absence, susceptibility to, 6 (1)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.24
Sift	Benign	0.78	T
Sift4G	Benign	0.18	T
Polyphen		0.22	B
Vest4		0.23
ClinPred		0.0049	T
GERP RS		2.6
Varity_R		0.10
gMVP		0.32
Mutation Taster		=98/2	polymorphism (auto)

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: rs61734410; hg19: chr16-1252369; COSMIC: COSV61998602; COSMIC: COSV61998602;