rs16847674

Variant names:

• chr1-201078007-G-A
• rs16847674
• NM_000069.3:c.1491C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-201078007-G-A
• chr1-201078007-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.1491C>T​(p.Asn497Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.0656 in 1,614,036 control chromosomes in the GnomAD database, including 4,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (902 hom., cov: 31)
  • Exomes 𝑓: 0.063 (3867 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 4.27
• Publications: 12 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):

• hypokalemic periodic paralysis, type 1

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital myopathy 18

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-201078007-G-A is Benign according to our data. Variant chr1-201078007-G-A is described in ClinVar as Benign. ClinVar VariationId is 254795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

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.1491C>T	p.Asn497Asn	synonymous	Exon 11 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.1491C>T	p.Asn497Asn	synonymous	Exon 11 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.1491C>T	p.Asn497Asn	synonymous	Exon 11 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.1491C>T	p.Asn497Asn	synonymous	Exon 11 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.0951 AC: 14472 AN: 152156 Hom.: 897 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0864

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.0563

Gnomad FIN AF: 0.0967

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0502

Gnomad OTH AF: 0.0883

GnomAD2 exomes AF: 0.0872 AC: 21936 AN: 251492 AF XY: 0.0819

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.0865

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.0965

Gnomad NFE exome AF: 0.0538

Gnomad OTH exome AF: 0.0721

GnomAD4 exome AF: 0.0625 AC: 91377 AN: 1461762 Hom.: 3867 Cov.: 35 AF XY: 0.0621 AC XY: 45127 AN XY: 727176

African (AFR) AF: 0.166 AC: 5545 AN: 33476

American (AMR) AF: 0.131 AC: 5837 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0893 AC: 2333 AN: 26126

East Asian (EAS) AF: 0.219 AC: 8686 AN: 39698

South Asian (SAS) AF: 0.0607 AC: 5235 AN: 86254

European-Finnish (FIN) AF: 0.0918 AC: 4903 AN: 53420

Middle Eastern (MID) AF: 0.128 AC: 741 AN: 5768

European-Non Finnish (NFE) AF: 0.0483 AC: 53760 AN: 1111904

Other (OTH) AF: 0.0718 AC: 4337 AN: 60392

GnomAD4 genome AF: 0.0953 AC: 14511 AN: 152274 Hom.: 902 Cov.: 31 AF XY: 0.0977 AC XY: 7274 AN XY: 74462

African (AFR) AF: 0.160 AC: 6637 AN: 41550

American (AMR) AF: 0.103 AC: 1576 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0864 AC: 300 AN: 3472

East Asian (EAS) AF: 0.192 AC: 991 AN: 5166

South Asian (SAS) AF: 0.0563 AC: 272 AN: 4828

European-Finnish (FIN) AF: 0.0967 AC: 1026 AN: 10614

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0502 AC: 3412 AN: 68016

Other (OTH) AF: 0.0936 AC: 198 AN: 2116

Alfa AF: 0.0797 Hom.: 479

Bravo AF: 0.101

Asia WGS AF: 0.123 AC: 427 AN: 3478

EpiCase AF: 0.0574

EpiControl AF: 0.0559

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Malignant hyperthermia, susceptibility to, 5 (3)
-	-	3	not specified (3)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)
-	-	1	not provided (1)
-	-	1	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.7
DANN	Benign	0.77
PhyloP100		4.3
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16847674; hg19: chr1-201047135; COSMIC: COSV62939562;