1-201110169-C-G

Variant names:

• chr1-201110169-C-G
• NM_000069.3:c.253G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000069.3(CACNA1S):​c.253G>C​(p.Gly85Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. G85S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28550956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.253G>C	p.Gly85Arg	missense_variant	Exon 2 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.253G>C	p.Gly85Arg	missense_variant	Exon 2 of 43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.253G>C	p.Gly85Arg	missense_variant	Exon 2 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461750 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727184

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	-0.56	.;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.45	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.023	.;B
Vest4		0.29
MutPred		0.43		Loss of ubiquitination at K88 (P = 0.0709);Loss of ubiquitination at K88 (P = 0.0709);
MVP		0.92
MPC		0.13
ClinPred		0.13	T
GERP RS		4.9
Varity_R		0.070
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-201079297;