1-201069522-C-T

Variant names:

• chr1-201069522-C-T
• rs139956524
• NM_000069.3:c.2440G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000069.3(CACNA1S):​c.2440G>A​(p.Ala814Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,592,980 control chromosomes in the GnomAD database, including 6 homozygotes. 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. A814P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 3.32
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024012804).
• BP6: Variant 1-201069522-C-T is Benign according to our data. Variant chr1-201069522-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294744.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00131 (200/152254) while in subpopulation NFE AF = 0.00237 (161/68024). AF 95% confidence interval is 0.00207. There are 0 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR,SD gene

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.2440G>A	p.Ala814Thr	missense	Exon 18 of 44	NP_000060.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.2440G>A	p.Ala814Thr	missense	Exon 18 of 44	ENSP00000355192.3
	CACNA1S	ENST00000367338.7	TSL:5	c.2440G>A	p.Ala814Thr	missense	Exon 18 of 43	ENSP00000356307.3
	CACNA1S	ENST00000681874.1		c.2440G>A	p.Ala814Thr	missense	Exon 18 of 43	ENSP00000505162.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00121 AC: 254 AN: 210546 AF XY: 0.00119

Gnomad AFR exome AF: 0.000293

Gnomad AMR exome AF: 0.000458

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000164

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00188

GnomAD4 exome AF: 0.00198 AC: 2846 AN: 1440726 Hom.: 6 Cov.: 31 AF XY: 0.00190 AC XY: 1357 AN XY: 714162

African (AFR) AF: 0.000269 AC: 9 AN: 33406

American (AMR) AF: 0.000580 AC: 23 AN: 39678

Ashkenazi Jewish (ASJ) AF: 0.00269 AC: 69 AN: 25614

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 38992

South Asian (SAS) AF: 0.000219 AC: 18 AN: 82094

European-Finnish (FIN) AF: 0.000134 AC: 7 AN: 52128

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5724

European-Non Finnish (NFE) AF: 0.00236 AC: 2605 AN: 1103208

Other (OTH) AF: 0.00184 AC: 110 AN: 59882

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74432

African (AFR) AF: 0.000457 AC: 19 AN: 41532

American (AMR) AF: 0.000850 AC: 13 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00237 AC: 161 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00179 Hom.: 2

Bravo AF: 0.00132

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00100 AC: 120

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	Malignant hyperthermia, susceptibility to, 5 (2)
-	-	1	CACNA1S-related disorder (1)
-	-	1	Hypokalemic periodic paralysis, type 1 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.024	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.0080	B
Vest4		0.36
MVP		0.90
MPC		0.10
ClinPred		0.045	T
GERP RS		2.7
Varity_R		0.12
gMVP		0.58
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139956524; hg19: chr1-201038650; COSMIC: COSV99054144;