chr1-201091737-G-A

Variant names:

• chr1-201091737-G-A
• rs2296383
• NM_000069.3:c.597C>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.597C>T​(p.Ile199Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 1,613,646 control chromosomes in the GnomAD database, including 143,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9766 hom., cov: 32)
  • Exomes 𝑓: 0.42 (134092 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.711
• Publications: 23 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 1-201091737-G-A is Benign according to our data. Variant chr1-201091737-G-A is described in ClinVar as Benign. ClinVar VariationId is 254852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.711 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.429 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.597C>T	p.Ile199Ile	synonymous	Exon 5 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.597C>T	p.Ile199Ile	synonymous	Exon 5 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.597C>T	p.Ile199Ile	synonymous	Exon 5 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.597C>T	p.Ile199Ile	synonymous	Exon 5 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49894 AN: 152006 Hom.: 9768 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.337

GnomAD2 exomes AF: 0.390 AC: 97845 AN: 251092 AF XY: 0.400

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.359

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.424 AC: 619082 AN: 1461522 Hom.: 134092 Cov.: 44 AF XY: 0.426 AC XY: 309402 AN XY: 727056

African (AFR) AF: 0.0957 AC: 3205 AN: 33478

American (AMR) AF: 0.352 AC: 15743 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 12159 AN: 26134

East Asian (EAS) AF: 0.389 AC: 15438 AN: 39676

South Asian (SAS) AF: 0.450 AC: 38841 AN: 86256

European-Finnish (FIN) AF: 0.373 AC: 19942 AN: 53412

Middle Eastern (MID) AF: 0.391 AC: 2256 AN: 5766

European-Non Finnish (NFE) AF: 0.438 AC: 486611 AN: 1111706

Other (OTH) AF: 0.412 AC: 24887 AN: 60382

GnomAD4 genome AF: 0.328 AC: 49904 AN: 152124 Hom.: 9766 Cov.: 32 AF XY: 0.327 AC XY: 24294 AN XY: 74364

African (AFR) AF: 0.109 AC: 4521 AN: 41526

American (AMR) AF: 0.349 AC: 5327 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1573 AN: 3470

East Asian (EAS) AF: 0.367 AC: 1895 AN: 5170

South Asian (SAS) AF: 0.438 AC: 2108 AN: 4818

European-Finnish (FIN) AF: 0.363 AC: 3842 AN: 10570

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29421 AN: 67972

Other (OTH) AF: 0.339 AC: 715 AN: 2108

Alfa AF: 0.395 Hom.: 27009

Bravo AF: 0.315

Asia WGS AF: 0.394 AC: 1371 AN: 3478

EpiCase AF: 0.430

EpiControl AF: 0.425

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	6.7
DANN	Benign	0.76
PhyloP100		-0.71
Mutation Taster		=99/1	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: rs2296383; hg19: chr1-201060865; COSMIC: COSV62936330;