2-199348705-G-T

Variant names:

• chr2-199348705-G-T
• rs863224917
• NM_001172509.2:c.1169C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001172509.2(SATB2):​c.1169C>A​(p.Thr390Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,421,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T390I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SATB2 NM_001172509.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.95
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• SATB2 associated disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr2-199348705-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 216996.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

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.1169C>A	p.Thr390Lys	missense	Exon 7 of 11	NP_001165980.1
	SATB2	NM_001172517.1		c.1169C>A	p.Thr390Lys	missense	Exon 8 of 12	NP_001165988.1
	SATB2	NM_015265.4		c.1169C>A	p.Thr390Lys	missense	Exon 8 of 12	NP_056080.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SATB2	ENST00000417098.6	TSL:2 MANE Select	c.1169C>A	p.Thr390Lys	missense	Exon 7 of 11	ENSP00000401112.1
	SATB2	ENST00000260926.9	TSL:1	c.1169C>A	p.Thr390Lys	missense	Exon 8 of 12	ENSP00000260926.5
	SATB2	ENST00000428695.6	TSL:1	c.815C>A	p.Thr272Lys	missense	Exon 5 of 9	ENSP00000388581.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1421404 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 702800

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32568

American (AMR) AF: 0.00 AC: 0 AN: 41296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.00 AC: 0 AN: 77916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091534

Other (OTH) AF: 0.00 AC: 0 AN: 58660

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.72		Gain of solvent accessibility (P = 0.012)
MVP		0.86
MPC		2.4
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.80
gMVP		0.93
Mutation Taster		=0/100	disease causing

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: rs863224917; hg19: chr2-200213428;