chr1-201051037-T-A

Variant names:

• chr1-201051037-T-A
• rs145910245
• NM_000069.3:c.4060A>T

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.4060A>T​(p.Thr1354Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,614,210 control chromosomes in the GnomAD database, including 34 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. T1354I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (33 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 3.14
• Publications: 26 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009345293).
• BP6: Variant 1-201051037-T-A is Benign according to our data. Variant chr1-201051037-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161208.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00335 (511/152342) while in subpopulation NFE AF = 0.00519 (353/68026). AF 95% confidence interval is 0.00474. There are 1 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 33 SD,AD,AR 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.4060A>T	p.Thr1354Ser	missense	Exon 33 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.4060A>T	p.Thr1354Ser	missense	Exon 33 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.4003A>T	p.Thr1335Ser	missense	Exon 32 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.4000A>T	p.Thr1334Ser	missense	Exon 32 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00519

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00264 AC: 663 AN: 251492 AF XY: 0.00260

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00438

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00499 AC: 7295 AN: 1461868 Hom.: 33 Cov.: 35 AF XY: 0.00473 AC XY: 3441 AN XY: 727234

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.00157 AC: 70 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00551 AC: 144 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00191 AC: 102 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00598 AC: 6653 AN: 1111990

Other (OTH) AF: 0.00492 AC: 297 AN: 60396

GnomAD4 genome AF: 0.00335 AC: 511 AN: 152342 Hom.: 1 Cov.: 33 AF XY: 0.00323 AC XY: 241 AN XY: 74498

African (AFR) AF: 0.00115 AC: 48 AN: 41586

American (AMR) AF: 0.00366 AC: 56 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00519 AC: 353 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00342 Hom.: 0

Bravo AF: 0.00322

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00236 AC: 287

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00480

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	19
DANN	Benign	0.33
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	-1.3	N
PhyloP100		3.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.6	N
REVEL	Uncertain	0.57
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.090	B
Vest4		0.28
MutPred		0.57		Gain of disorder (P = 0.086)
MVP		0.87
MPC		0.093
ClinPred		0.034	T
GERP RS		4.4
Varity_R		0.22
gMVP		0.58
Mutation Taster		=93/7	polymorphism

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: rs145910245; hg19: chr1-201020165;