rs1553493553

Variant names:

• chr2-199368631-C-T
• rs1553493553
• NM_001172509.2:c.674G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001172509.2(SATB2):​c.674G>A​(p.Trp225*) variant causes a stop gained 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SATB2 NM_001172509.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-199368631-C-T is Pathogenic according to our data. Variant chr2-199368631-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437864.

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.674G>A	p.Trp225*	stop_gained	Exon 6 of 11	NP_001165980.1	Q9UPW6-1
	SATB2	NM_001172517.1		c.674G>A	p.Trp225*	stop_gained	Exon 7 of 12	NP_001165988.1	Q59FT3
	SATB2	NM_015265.4		c.674G>A	p.Trp225*	stop_gained	Exon 7 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.674G>A	p.Trp225*	stop_gained	Exon 6 of 11	ENSP00000401112.1	Q9UPW6-1
	SATB2	ENST00000260926.9	TSL:1	c.674G>A	p.Trp225*	stop_gained	Exon 7 of 12	ENSP00000260926.5	Q9UPW6-1
	SATB2	ENST00000428695.6	TSL:1	c.347-19458G>A		intron	N/A	ENSP00000388581.1	Q9UPW6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Chromosome 2q32-q33 deletion syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.9
Vest4		0.76
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553493553; hg19: chr2-200233354;