rs16847623

Variant names:

• chr1-201066301-G-A
• rs16847623
• NM_000069.3:c.2673C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000069.3(CACNA1S):​c.2673C>T​(p.Ser891Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00778 in 1,611,918 control chromosomes in the GnomAD database, including 335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (154 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (181 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -6.39
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• malignant hyperthermia, susceptibility to, 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-201066301-G-A is Benign according to our data. Variant chr1-201066301-G-A is described in ClinVar as Benign. ClinVar VariationId is 254819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0793 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.2673C>T	p.Ser891Ser	synonymous	Exon 21 of 44	NP_000060.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.2673C>T	p.Ser891Ser	synonymous	Exon 21 of 44	ENSP00000355192.3
	CACNA1S	ENST00000367338.7	TSL:5	c.2673C>T	p.Ser891Ser	synonymous	Exon 21 of 43	ENSP00000356307.3
	CACNA1S	ENST00000681874.1		c.2613C>T	p.Ser871Ser	synonymous	Exon 20 of 43	ENSP00000505162.1

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4124 AN: 151932 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.0816

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00499

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.0293

GnomAD2 exomes AF: 0.0109 AC: 2729 AN: 249768 AF XY: 0.00966

Gnomad AFR exome AF: 0.0850

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000499

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.00576 AC: 8410 AN: 1459868 Hom.: 181 Cov.: 32 AF XY: 0.00568 AC XY: 4128 AN XY: 726334

African (AFR) AF: 0.0869 AC: 2909 AN: 33476

American (AMR) AF: 0.0142 AC: 637 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 443 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00625 AC: 539 AN: 86256

European-Finnish (FIN) AF: 0.000136 AC: 7 AN: 51468

Middle Eastern (MID) AF: 0.0286 AC: 165 AN: 5768

European-Non Finnish (NFE) AF: 0.00268 AC: 2978 AN: 1111972

Other (OTH) AF: 0.0121 AC: 729 AN: 60382

GnomAD4 genome AF: 0.0272 AC: 4130 AN: 152050 Hom.: 154 Cov.: 32 AF XY: 0.0264 AC XY: 1962 AN XY: 74328

African (AFR) AF: 0.0816 AC: 3381 AN: 41424

American (AMR) AF: 0.0225 AC: 344 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00458 AC: 22 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00371 AC: 252 AN: 67974

Other (OTH) AF: 0.0290 AC: 61 AN: 2106

Alfa AF: 0.0178 Hom.: 63

Bravo AF: 0.0326

Asia WGS AF: 0.00577 AC: 21 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.48
DANN	Benign	0.63
PhyloP100		-6.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16847623; hg19: chr1-201035429; COSMIC: COSV62939819;