chr2-199308804-C-T

Variant names:

• chr2-199308804-C-T
• rs1064795530
• NM_001172509.2:c.1696G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 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 (★★). ClinVar reports functional evidence for this variant: "SCV000571436: 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); SCV003525185: Experimental studies have shown that this missense change affects SATB2 function (PMID:28151491).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: SATB2 NM_001172509.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.61
• Publications: 6 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000571436: 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); SCV003525185: Experimental studies have shown that this missense change affects SATB2 function (PMID: 28151491).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-199308804-C-T is Pathogenic according to our data. Variant chr2-199308804-C-T is described in ClinVar as Pathogenic. ClinVar VariationId 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.

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.1696G>A	p.Glu566Lys	missense	Exon 10 of 11	NP_001165980.1	Q9UPW6-1
	SATB2	NM_001172517.1		c.1696G>A	p.Glu566Lys	missense	Exon 11 of 12	NP_001165988.1	Q59FT3
	SATB2	NM_015265.4		c.1696G>A	p.Glu566Lys	missense	Exon 11 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.1696G>A	p.Glu566Lys	missense	Exon 10 of 11	ENSP00000401112.1	Q9UPW6-1
	SATB2	ENST00000260926.9	TSL:1	c.1696G>A	p.Glu566Lys	missense	Exon 11 of 12	ENSP00000260926.5	Q9UPW6-1
	SATB2	ENST00000428695.6	TSL:1	c.1342G>A	p.Glu448Lys	missense	Exon 8 of 9	ENSP00000388581.1	Q9UPW6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Chromosome 2q32-q33 deletion syndrome (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.22
Sift	Uncertain	0.017	D
Sift4G	Benign	0.13	T
Polyphen		0.99	D
Vest4		0.49
MutPred		0.43		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
Mutation Taster		=6/94	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: rs1064795530; hg19: chr2-200173527; COSMIC: COSV53477421; COSMIC: COSV53477421;