rs1064795530

Positions:

• chr2-199308804-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2 PP2 PP5_Very_Strong BP4

The NM_001172509.2(SATB2):​c.1696G>A​(p.Glu566Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SATB2 NM_001172509.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.61

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 2-199308804-C-T is Pathogenic according to our data. Variant chr2-199308804-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 422062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27782565). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SATB2	NM_001172509.2	c.1696G>A	p.Glu566Lys	missense_variant	10/11	ENST00000417098.6	NP_001165980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SATB2	ENST00000417098.6	c.1696G>A	p.Glu566Lys	missense_variant	10/11	2	NM_001172509.2	ENSP00000401112	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chromosome 2q32-q33 deletion syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SATB2 function (PMID: 28151491). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SATB2 protein function. ClinVar contains an entry for this variant (Variation ID: 422062). This missense change has been observed in individual(s) with clinical features of SATB2-related conditions (PMID: 28151491). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 566 of the SATB2 protein (p.Glu566Lys). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 22, 2024

Published functional studies suggest this variant impairs interaction with chromatin, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 28151491); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28151491, 33057194, 35982159, 35241104) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;T;T;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D;.;.;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.7	N;.;N;N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.017	D;.;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.99	D;.;.;D;.;D
Vest4		0.49
MutPred		0.43		Loss of helix (P = 3e-04);.;.;Loss of helix (P = 3e-04);.;Loss of helix (P = 3e-04);
MVP		0.50
MPC		1.3
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.26
gMVP		0.90

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: rs1064795530; hg19: chr2-200173527; COSMIC: COSV53477421; COSMIC: COSV53477421;