1-201110107-C-T

Variant names:

• chr1-201110107-C-T
• rs1325310
• NM_000069.3:c.258+57G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.258+57G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,500,426 control chromosomes in the GnomAD database, including 67,305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7095 hom., cov: 32)
  • Exomes 𝑓: 0.29 (60210 hom.)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.0420
• 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):

• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-201110107-C-T is Benign according to our data. Variant chr1-201110107-C-T is described in ClinVar as Benign. ClinVar VariationId is 17628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.258+57G>A		intron_variant	Intron 2 of 43	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.258+57G>A		intron_variant	Intron 2 of 42		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.258+57G>A		intron_variant	Intron 2 of 43	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44808 AN: 151928 Hom.: 7098 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.313

GnomAD4 exome AF: 0.286 AC: 384991 AN: 1348380 Hom.: 60210 AF XY: 0.288 AC XY: 194752 AN XY: 676598

African (AFR) AF: 0.283 AC: 8836 AN: 31182

American (AMR) AF: 0.438 AC: 19520 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6489 AN: 25470

East Asian (EAS) AF: 0.650 AC: 25449 AN: 39172

South Asian (SAS) AF: 0.403 AC: 33870 AN: 84002

European-Finnish (FIN) AF: 0.251 AC: 13333 AN: 53224

Middle Eastern (MID) AF: 0.263 AC: 1462 AN: 5550

European-Non Finnish (NFE) AF: 0.257 AC: 259440 AN: 1008620

Other (OTH) AF: 0.293 AC: 16592 AN: 56616

GnomAD4 genome AF: 0.295 AC: 44810 AN: 152046 Hom.: 7095 Cov.: 32 AF XY: 0.299 AC XY: 22204 AN XY: 74326

African (AFR) AF: 0.285 AC: 11830 AN: 41482

American (AMR) AF: 0.379 AC: 5788 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 837 AN: 3470

East Asian (EAS) AF: 0.622 AC: 3196 AN: 5136

South Asian (SAS) AF: 0.413 AC: 1979 AN: 4796

European-Finnish (FIN) AF: 0.236 AC: 2498 AN: 10604

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17698 AN: 67962

Other (OTH) AF: 0.309 AC: 650 AN: 2106

Alfa AF: 0.269 Hom.: 6582

Bravo AF: 0.306

Asia WGS AF: 0.472 AC: 1638 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Thyrotoxic periodic paralysis, susceptibility to, 1 Other:1

Mar 01, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.76
PhyloP100		-0.042
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: rs1325310; hg19: chr1-201079235; COSMIC: COSV62942876; COSMIC: COSV62942876;