rs79011683

Variant names:

• chr1-201048677-A-C
• rs79011683
• NM_000069.3:c.4346T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-201048677-A-C
• chr1-201048677-A-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP4_Strong BP6_Moderate

The NM_000069.3(CACNA1S):​c.4346T>G​(p.Val1449Gly) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts 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. V1449M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Benign criteria provided, single submitter U:1 B:2
• Conservation: PhyloP100: 9.30
• Publications: 8 publications found

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]

CACNA1S Gene-Disease associations (from GenCC):

• congenital myopathy 18

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypokalemic periodic paralysis, type 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• malignant hyperthermia, susceptibility to, 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• congenital myopathy

  Inheritance: SD, AR, AD Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0042477846).
• BP6: Variant 1-201048677-A-C is Benign according to our data. Variant chr1-201048677-A-C is described in ClinVar as Benign. ClinVar VariationId is 294720.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000069.3. 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
	CACNA1S	NM_000069.3	MANE Select	c.4346T>G	p.Val1449Gly	missense	Exon 36 of 44	NP_000060.2	Q13698

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.4346T>G	p.Val1449Gly	missense	Exon 36 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.4289T>G	p.Val1430Gly	missense	Exon 35 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.4286T>G	p.Val1429Gly	missense	Exon 35 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.000977 AC: 148 AN: 151518 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00204

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.208 AC: 46557 AN: 224358 AF XY: 0.212

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.189

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.142

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0206 AC: 29743 AN: 1441400 Hom.: 0 Cov.: 32 AF XY: 0.0246 AC XY: 17629 AN XY: 715304

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0248 AC: 823 AN: 33132

American (AMR) AF: 0.0934 AC: 3997 AN: 42790

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 1019 AN: 25424

East Asian (EAS) AF: 0.0428 AC: 1673 AN: 39070

South Asian (SAS) AF: 0.0477 AC: 3939 AN: 82650

European-Finnish (FIN) AF: 0.0848 AC: 4106 AN: 48424

Middle Eastern (MID) AF: 0.0514 AC: 250 AN: 4864

European-Non Finnish (NFE) AF: 0.0118 AC: 13016 AN: 1105346

Other (OTH) AF: 0.0154 AC: 920 AN: 59700

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000989 AC: 150 AN: 151620 Hom.: 0 Cov.: 33 AF XY: 0.00127 AC XY: 94 AN XY: 74050

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000144 AC: 6 AN: 41538

American (AMR) AF: 0.000459 AC: 7 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00204 AC: 7 AN: 3436

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00181 AC: 122 AN: 67508

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0245 Hom.: 0

ExAC AF: 0.220 AC: 25067

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hypokalemic periodic paralysis (1)
-	-	1	Malignant hyperthermia of anesthesia (1)
-	1	-	Malignant hyperthermia, susceptibility to, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.3
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.21
MPC		0.56
ClinPred		0.066	T
GERP RS		5.2
Varity_R		0.91
gMVP		0.88
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs79011683; hg19: chr1-201017805; COSMIC: COSV62935765;