rs183195890

Variant names:

• chr1-201044407-G-A
• rs183195890
• NM_000069.3:c.4718C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-201044407-G-A
• chr1-201044407-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_000069.3(CACNA1S):​c.4718C>T​(p.Thr1573Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000421 in 1,613,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1573S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 9.54
• Publications: 5 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.124114275).
• BP6: Variant 1-201044407-G-A is Benign according to our data. Variant chr1-201044407-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541073.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000445 (651/1461478) while in subpopulation AMR AF = 0.000648 (29/44720). AF 95% confidence interval is 0.000478. There are 0 homozygotes in GnomAdExome4. There are 317 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.4718C>T	p.Thr1573Met	missense	Exon 39 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.4718C>T	p.Thr1573Met	missense	Exon 39 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.4661C>T	p.Thr1554Met	missense	Exon 38 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.4658C>T	p.Thr1553Met	missense	Exon 38 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151974 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000363 AC: 91 AN: 250984 AF XY: 0.000405

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000445 AC: 651 AN: 1461478 Hom.: 0 Cov.: 31 AF XY: 0.000436 AC XY: 317 AN XY: 727056

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000648 AC: 29 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000513 AC: 570 AN: 1111930

Other (OTH) AF: 0.000497 AC: 30 AN: 60386

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152092 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74352

African (AFR) AF: 0.0000723 AC: 3 AN: 41490

American (AMR) AF: 0.000262 AC: 4 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67952

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000253

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	2	Malignant hyperthermia, susceptibility to, 5 (2)
-	-	1	CACNA1S-related disorder (1)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Hypokalemic periodic paralysis, type 1 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1 (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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.4	L
PhyloP100		9.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.055	T
Polyphen		0.93	P
Vest4		0.41
MVP		0.96
MPC		0.40
ClinPred		0.14	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.59
Mutation Taster		=88/12	polymorphism

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: rs183195890; hg19: chr1-201013535; COSMIC: COSV105918481; COSMIC: COSV105918481;