rs863224917

chr2-199348705-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001172509.2(SATB2):c.1169C>T(p.Thr390Ile) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SATB2 NM_001172509.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.95

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001172509.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SATB2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 2-199348705-G-A is Pathogenic according to our data. Variant chr2-199348705-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216996.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-199348705-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-199348705-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SATB2	NM_001172509.2	c.1169C>T	p.Thr390Ile	missense_variant	7/11	ENST00000417098.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SATB2	ENST00000417098.6	c.1169C>T	p.Thr390Ile	missense_variant	7/11	2	NM_001172509.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chromosome 2q32-q33 deletion syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Jul 22, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;T;D;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.6	M;.;.;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.8	D;.;D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;D
Vest4		0.95
MutPred		0.71		Loss of phosphorylation at T390 (P = 0.0354);.;.;Loss of phosphorylation at T390 (P = 0.0354);.;Loss of phosphorylation at T390 (P = 0.0354);
MVP		0.86
MPC		2.3
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.57
gMVP		0.89

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: rs863224917; hg19: chr2-200213428;