NM_001172509.2:c.1285C>T

Variant names:

• chr2-199328799-G-A
• rs886041847
• NM_001172509.2:c.1285C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001172509.2(SATB2):​c.1285C>T​(p.Arg429*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SATB2 NM_001172509.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.19

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]

ENSG00000257045 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 2-199328799-G-A is Pathogenic according to our data. Variant chr2-199328799-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-199328799-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-199328799-G-A is described in Lovd as [Pathogenic]. Variant chr2-199328799-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SATB2	NM_001172509.2	c.1285C>T	p.Arg429*	stop_gained	Exon 8 of 11	ENST00000417098.6	NP_001165980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SATB2	ENST00000417098.6	c.1285C>T	p.Arg429*	stop_gained	Exon 8 of 11	2	NM_001172509.2	ENSP00000401112.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chromosome 2q32-q33 deletion syndrome Pathogenic:4

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg429*) in the SATB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SATB2 are known to be pathogenic (PMID: 25885067). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Glass syndrome (PMID: 28151491). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280687). For these reasons, this variant has been classified as Pathogenic. -

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2022

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Mar 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); Nonsense variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29436146, 31021519, 28151491, 29739092, 32765914, 32446642) -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neurodevelopmental abnormality Pathogenic:1

Dec 09, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The patient is heterozygous (de novo) for the variant. ACMG criteria used: PS2, PS4, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.89
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs886041847; hg19: chr2-200193522; COSMIC: COSV105026214;