rs56271007

Positions:

• chr17-63714053-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001003787.4(STRADA):​c.179G>T​(p.Ser60Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: STRADA NM_001003787.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.32

Genes affected

STRADA (HGNC:30172): (STE20 related adaptor alpha) The protein encoded by this gene contains a STE20-like kinase domain, but lacks several residues that are critical for catalytic activity, so it is termed a 'pseudokinase'. The protein forms a heterotrimeric complex with serine/threonine kinase 11 (STK11, also known as LKB1) and the scaffolding protein calcium binding protein 39 (CAB39, also known as MO25). The protein activates STK11 leading to the phosphorylation of both proteins and excluding STK11 from the nucleus. The protein is necessary for STK11-induced G1 cell cycle arrest. A mutation in this gene has been shown to result in polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described but their full-length nature is not known. [provided by RefSeq, Sep 2009]

ENSG00000125695 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14597449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRADA	NM_001003787.4	c.179G>T	p.Ser60Ile	missense_variant	5/13	ENST00000336174.12	NP_001003787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STRADA	ENST00000336174.12	c.179G>T	p.Ser60Ile	missense_variant	5/13	1	NM_001003787.4	ENSP00000336655.6
ENSG00000125695	ENST00000580553.1	n.*217G>T		non_coding_transcript_exon_variant	5/12	5		ENSP00000464100.1
ENSG00000125695	ENST00000580553.1	n.*217G>T		3_prime_UTR_variant	5/12	5		ENSP00000464100.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Childhood epilepsy with centrotemporal spikes Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Polyhydramnios, megalencephaly, and symptomatic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with Rolandic epilepsy (PMID: 29358611). ClinVar contains an entry for this variant (Variation ID: 433135). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with isoleucine at codon 60 of the STRADA protein (p.Ser60Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.056	.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;.;D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.41	.;.;N;.;.;N;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.12	.;.;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.21	.;.;T;T;.;T;.;.;T;.;.;.;.;.;.;.;T;T;.;.;.;.;.;T;.;.;.;.;.;.;.
Polyphen		0.029, 0.017, 0.0050, 0.053	.;B;B;B;B;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.
Vest4		0.53, 0.42, 0.39, 0.48, 0.50, 0.41, 0.41
MutPred		0.16		.;.;Loss of disorder (P = 0.0062);.;.;.;.;.;.;.;Loss of disorder (P = 0.0062);.;Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);Loss of disorder (P = 0.0062);.;.;Loss of disorder (P = 0.0062);.;Loss of disorder (P = 0.0062);.;.;.;.;.;Loss of disorder (P = 0.0062);.;.;.;.;
MVP		0.63
MPC		1.0
ClinPred		0.79	D
GERP RS		3.9
Varity_R		0.44
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs56271007; hg19: chr17-61791413;