1-201051599-A-G

Variant names:

• chr1-201051599-A-G
• rs3767498
• NM_000069.3:c.3954-456T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000069.3(CACNA1S):​c.3954-456T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 152,152 control chromosomes in the GnomAD database, including 46,855 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.78 (46855 hom., cov: 32)
• Consequence: CACNA1S NM_000069.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.555
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.3954-456T>C		intron_variant	Intron 32 of 43	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.3897-456T>C		intron_variant	Intron 31 of 42		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.3954-456T>C		intron_variant	Intron 32 of 43	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes AF: 0.776 AC: 117927 AN: 152034 Hom.: 46790 Cov.: 32

Gnomad AFR AF: 0.919

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.801

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.771

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.776 AC: 118052 AN: 152152 Hom.: 46855 Cov.: 32 AF XY: 0.783 AC XY: 58242 AN XY: 74366

African (AFR) AF: 0.919 AC: 38162 AN: 41526

American (AMR) AF: 0.802 AC: 12258 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2578 AN: 3472

East Asian (EAS) AF: 0.993 AC: 5140 AN: 5174

South Asian (SAS) AF: 0.874 AC: 4217 AN: 4824

European-Finnish (FIN) AF: 0.770 AC: 8142 AN: 10570

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.666 AC: 45249 AN: 67976

Other (OTH) AF: 0.774 AC: 1634 AN: 2112

Alfa AF: 0.710 Hom.: 125019

Bravo AF: 0.786

Asia WGS AF: 0.927 AC: 3221 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.7
DANN	Benign	0.53
PhyloP100		-0.56
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

Other links and lift over

dbSNP: rs3767498; hg19: chr1-201020727;