16-1219071-G-T

Position:

• chr16-1219071-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021098.3(CACNA1H):​c.5989G>T​(p.Ala1997Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,397,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1997T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11500418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5989G>T	p.Ala1997Ser	missense_variant	34/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5989G>T	p.Ala1997Ser	missense_variant	34/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5971G>T	p.Ala1991Ser	missense_variant	32/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5950G>T	p.Ala1984Ser	missense_variant	34/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2227G>T	p.Ala743Ser	missense_variant	16/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2179G>T	p.Ala727Ser	missense_variant	17/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2161G>T	p.Ala721Ser	missense_variant	16/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1037G>T		non_coding_transcript_exon_variant	34/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3807G>T		non_coding_transcript_exon_variant	34/35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*1037G>T		3_prime_UTR_variant	34/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3807G>T		3_prime_UTR_variant	34/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397448 Hom.: 0 Cov.: 34 AF XY: 0.00000290 AC XY: 2 AN XY: 689272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.043
DANN	Benign	0.66
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.36	T;T;T;.
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	-0.0062	T
MutationAssessor	Benign	1.2	L;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.16	N;.;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.59	T;.;T;T
Sift4G	Benign	0.76	T;.;T;T
Polyphen		0.043	B;.;B;B
Vest4		0.087
MutPred		0.14		Gain of glycosylation at A1997 (P = 0.0155);.;.;.;
MVP		0.81
ClinPred		0.10	T
GERP RS		-3.9
Varity_R		0.086
gMVP		0.22

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: rs376628149; hg19: chr16-1269071;