rs1057521083

Variant names:

• chr2-199348709-G-A
• rs1057521083
• NM_001172509.2:c.1165C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 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 (★★). ClinVar reports functional evidence for this variant: "SCV000932629: Experimental studies have shown that this missense change alters sub-cellular localization and chromatin association ability of the protein (PMID:28151491)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R389H) 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:14 O:1
• Conservation: PhyloP100: 6.63
• Publications: 10 publications found

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]

SATB2 Gene-Disease associations (from GenCC):

• chromosome 2q32-q33 deletion syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• SATB2 associated disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000932629: Experimental studies have shown that this missense change alters sub-cellular localization and chromatin association ability of the protein (PMID: 28151491).; SCV004176151: Functional studies of p.(Arg389Cys) suggest changes in protein function [PMID: 28151491].; SCV002769396: "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)."
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1723662.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 381575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172509.2. 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
	SATB2	NM_001172509.2	MANE Select	c.1165C>T	p.Arg389Cys	missense	Exon 7 of 11	NP_001165980.1	Q9UPW6-1
	SATB2	NM_001172517.1		c.1165C>T	p.Arg389Cys	missense	Exon 8 of 12	NP_001165988.1	Q59FT3
	SATB2	NM_015265.4		c.1165C>T	p.Arg389Cys	missense	Exon 8 of 12	NP_056080.1	Q9UPW6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SATB2	ENST00000417098.6	TSL:2 MANE Select	c.1165C>T	p.Arg389Cys	missense	Exon 7 of 11	ENSP00000401112.1	Q9UPW6-1
	SATB2	ENST00000260926.9	TSL:1	c.1165C>T	p.Arg389Cys	missense	Exon 8 of 12	ENSP00000260926.5	Q9UPW6-1
	SATB2	ENST00000428695.6	TSL:1	c.811C>T	p.Arg271Cys	missense	Exon 5 of 9	ENSP00000388581.1	Q9UPW6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Chromosome 2q32-q33 deletion syndrome (11)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	SATB2 associated disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.028	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.6
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.70		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
Mutation Taster		=0/100	disease causing (ClinVar)

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