rs1057521083

Positions:

• chr2-199348709-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001172509.2(SATB2):​c.1165C>T​(p.Arg389Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R389L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SATB2 NM_001172509.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 6.63

Genes affected

SATB2 (HGNC:21637): (SATB homeobox 2) This gene encodes a DNA binding protein that specifically binds nuclear matrix attachment regions. The encoded protein is involved in transcription regulation and chromatin remodeling. Defects in this gene are associated with isolated cleft palate and cognitive disability. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a DNA_binding_region CUT 1 (size 87) in uniprot entity SATB2_HUMAN there are 26 pathogenic changes around while only 1 benign (96%) in NM_001172509.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-199348708-C-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SATB2. . Gene score misZ 4.0511 (greater than the threshold 3.09). Trascript score misZ 5.5168 (greater than threshold 3.09). GenCC has associacion of gene with chromosome 2q32-q33 deletion syndrome, SATB2 associated disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 2-199348709-G-A is Pathogenic according to our data. Variant chr2-199348709-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 381575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-199348709-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-199348709-G-A is described in Lovd as [Pathogenic]. Variant chr2-199348709-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SATB2	NM_001172509.2	c.1165C>T	p.Arg389Cys	missense_variant	7/11	ENST00000417098.6	NP_001165980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SATB2	ENST00000417098.6	c.1165C>T	p.Arg389Cys	missense_variant	7/11	2	NM_001172509.2	ENSP00000401112	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chromosome 2q32-q33 deletion syndrome Pathogenic:8 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 10, 2021	_x000D_ Criteria applied: PS2, PM5_STR, PS4_MOD, PM2_SUP, PP2, PP3 -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2018	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg389 amino acid residue in SATB2. Other variant that disrupts this residue has been observed in affected individuals (PMID: 28151491), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change alters sub-cellular localization and chromatin association ability of the protein (PMID: 28151491). This variant has been observed to be de novo in an individual affected with SATB2-related disease (PMID: 28151491). ClinVar contains an entry for this variant (Variation ID: 381575). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 389 of the SATB2 protein (p.Arg389Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Apr 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 15, 2023	The c.1165C>T variant in SATB2 has previously been reported in multiple individuals with SATB2-associated syndrome [PMID: 29436146, 31021519, 28151491, 33274544] and it has been deposited in ClinVar [ClinVar ID: 381575] as Pathogenic by multiple submitters as de novo in affected individuals. The c.1165C>T variant in SATB2 is absent in population databases (gnomADv2.1, gnomADv3.1, BRAVO-TOPMed, All of Us) suggesting it is not a common benign variant in the populations represented in those databases. The c.1165C>T variant is located in exon 7 of this 11-exon gene and is predicted to replace an evolutionarily conserved arginine amino acid with cystine at position 389 in the encoded protein. The c.1165C>T variant in SATB2 is located within the CUT1 critical domain where multiple pathogenic missense variants have been reported [PMID: 31021519, 29436146]. In silico predictions are in favor of the damaging effect for the p.(Arg389Cys) variant [(CADD v1.6 = 32, REVEL = 0.909)]. Functional studies of p.(Arg389Cys) suggest changes in protein function [PMID: 28151491]. Different missense variant affecting the same amino acid residue have been reported in the literature [c.1166G>T: p.(Arg389Leu); PMID: 31021519, 28151491] and ClinVar [p.(Arg389leu), ClinVar ID: 1526096; p.(Arg389His), ClinVar ID: 1723662; p.(Arg389Pro), ClinVar ID: 2430097] in individuals with SATB2-associated syndrome. Based on available evidence this de novo c.1165C>T p.(Arg389Cys) variant identified in SATB2 is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Mar 16, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2022	Reported previously in an individual with cleft palate, congenital myopia, global developmental delay, and micrognathia, as well as in the de novo state in an individual with intellectual disability, developmental delay, behavioral problems, and Pierre-Robin sequence (Trakadis et al., 2014; Bengani et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30945278, 24884844, 28151491, 29436146, 33726816, 31785789, 33274544, 34234817, 32446642) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 16, 2017	- -

SATB2 associated disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SATB2-related developmental disorder. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. The variant is located in the CUT domain in which there is a cluster of pathogenic variants. Additionally, this region has high missense contraint (Decipher). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Arg389Leu) variant has been identified in two patients with SATB2-related developmental disorder (PMID 31021519) and the p.(Arg389His) variant listed as likely pathogenic in a patient with Glass syndrome (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in at least 10 unrelated patients with SATB2-related developmental disorder and de novo inheritance has been confirmed in at least one patient (PMIDs: 31021519, 28151491, ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Nuclear localization studies have shown that this variant results in a more diffuse pattern than the wildtype and a marked increase in the proportion of soluble fraction of the protein (PMID: 28151491). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;.;T;D;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;.;.;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D
MetaSVM	Uncertain	0.028	D
MutationAssessor	Pathogenic	3.0	M;.;.;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.2	D;.;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;D
Vest4		0.96
MutPred		0.70		Loss of MoRF binding (P = 0.0096);.;.;Loss of MoRF binding (P = 0.0096);.;Loss of MoRF binding (P = 0.0096);
MVP		0.87
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.88

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: rs1057521083; hg19: chr2-200213432; COSMIC: COSV53481896;