rs41267497

Variant names:

• chr1-201043469-G-A
• rs41267497
• NM_000069.3:c.4860C>T
• CACNA1S p.Pro1620Pro

Your query was ambiguous. Multiple possible variants found:

• chr1-201043469-G-A
• chr1-201043469-G-C
• chr1-201043469-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000069.3(CACNA1S):​c.4860C>T​(p.Pro1620Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,800 control chromosomes in the GnomAD database, including 18,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1620P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (1166 hom., cov: 31)
  • Exomes 𝑓: 0.14 (17216 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.20
• Publications: 11 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), Ambry Genetics, 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: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Illumina
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-201043469-G-A is Benign according to our data. Variant chr1-201043469-G-A is described in ClinVar as Benign. ClinVar VariationId is 254841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 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.4860C>T	p.Pro1620Pro	synonymous	Exon 40 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.4860C>T	p.Pro1620Pro	synonymous	Exon 40 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.4803C>T	p.Pro1601Pro	synonymous	Exon 39 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.4800C>T	p.Pro1600Pro	synonymous	Exon 39 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15883 AN: 151930 Hom.: 1167 Cov.: 31

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.0901

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.105 AC: 26402 AN: 251320 AF XY: 0.105

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.0672

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.144 AC: 210454 AN: 1461752 Hom.: 17216 Cov.: 33 AF XY: 0.140 AC XY: 102151 AN XY: 727178

African (AFR) AF: 0.0234 AC: 785 AN: 33478

American (AMR) AF: 0.0697 AC: 3117 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2797 AN: 26132

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39680

South Asian (SAS) AF: 0.0267 AC: 2299 AN: 86236

European-Finnish (FIN) AF: 0.131 AC: 6979 AN: 53418

Middle Eastern (MID) AF: 0.0765 AC: 441 AN: 5768

European-Non Finnish (NFE) AF: 0.168 AC: 186751 AN: 1111924

Other (OTH) AF: 0.120 AC: 7274 AN: 60394

GnomAD4 genome AF: 0.104 AC: 15880 AN: 152048 Hom.: 1166 Cov.: 31 AF XY: 0.101 AC XY: 7472 AN XY: 74298

African (AFR) AF: 0.0296 AC: 1229 AN: 41480

American (AMR) AF: 0.0899 AC: 1374 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 366 AN: 3470

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5158

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4820

European-Finnish (FIN) AF: 0.125 AC: 1324 AN: 10558

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11004 AN: 67966

Other (OTH) AF: 0.109 AC: 230 AN: 2114

Alfa AF: 0.128 Hom.: 869

Bravo AF: 0.101

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.161

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Malignant hyperthermia, susceptibility to, 5 (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	-0.87
CADD	Benign	0.17
DANN	Benign	0.40
PhyloP100		-1.2
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41267497;

hg19: chr1-201012597;

COSMIC: COSV108208485;

COSMIC: COSV108208485;