rs59103647

Variant names:

• chr16-1220557-G-C
• rs59103647
• NM_021098.3:c.6625G>C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.6625G>C​(p.Ala2209Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,531,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.249

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

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.093827456).
• BP6: Variant 16-1220557-G-C is Benign according to our data. Variant chr16-1220557-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460172.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00021 (32/152048) while in subpopulation NFE AF= 0.000427 (29/67936). AF 95% confidence interval is 0.000304. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6625G>C	p.Ala2209Pro	missense_variant	Exon 35 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6625G>C	p.Ala2209Pro	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.6607G>C	p.Ala2203Pro	missense_variant	Exon 33 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.6586G>C	p.Ala2196Pro	missense_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2863G>C	p.Ala955Pro	missense_variant	Exon 17 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2815G>C	p.Ala939Pro	missense_variant	Exon 18 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2797G>C	p.Ala933Pro	missense_variant	Exon 17 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1673G>C		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4443G>C		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*1673G>C		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4443G>C		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000427

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000238 AC: 40 AN: 167994 Hom.: 0 AF XY: 0.000207 AC XY: 19 AN XY: 91872

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.0000957

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.000319 AC: 440 AN: 1379032 Hom.: 0 Cov.: 35 AF XY: 0.000311 AC XY: 211 AN XY: 679326

Gnomad4 AFR exome AF: 0.0000659

Gnomad4 AMR exome AF: 0.000102

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000210

Gnomad4 NFE exome AF: 0.000389

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74272

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000427

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000558 AC: 4

ExAC AF: 0.000188 AC: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Jun 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6625G>C (p.A2209P) alteration is located in exon 35 (coding exon 34) of the CACNA1H gene. This alteration results from a G to C substitution at nucleotide position 6625, causing the alanine (A) at amino acid position 2209 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Jan 21, 2025

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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.6
DANN	Benign	0.82
DEOGEN2	Benign	0.077	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.57	T;T;T;.
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.19	N;.;N;N
REVEL	Benign	0.10
Sift	Benign	0.31	T;.;T;T
Sift4G	Benign	0.40	T;.;T;T
Polyphen		0.0	B;.;P;P
Vest4		0.12
MVP		0.59
ClinPred		0.10	T
GERP RS		-3.5
Varity_R		0.10
gMVP		0.097

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

Publications

LitVar

Other links and lift over

dbSNP: rs59103647; hg19: chr16-1270557;