dbSNP rs137853127: SATB2:p.Arg239* (chr2-199349159-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001172509.2(SATB2):c.715C>T(p.Arg239*) 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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SATB2
NM_001172509.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 2.86

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 2-199349159-G-A is Pathogenic according to our data. Variant chr2-199349159-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-199349159-G-A is described in Lovd as [Pathogenic]. Variant chr2-199349159-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SATB2	NM_001172509.2 link	c.715C>T	p.Arg239*	stop_gained	Exon 7 of 11	ENST00000417098.6	NP_001165980.1	Q9UPW6-1A0A024R3U6B3KPQ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SATB2	ENST00000417098.6 link	c.715C>T	p.Arg239*	stop_gained	Exon 7 of 11	2	NM_001172509.2	ENSP00000401112.1		Q9UPW6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460450

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726528

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Chromosome 2q32-q33 deletion syndrome

Pathogenic:5Other:1

May 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2519). This premature translational stop signal has been observed in individuals with a clinical phenotype including cleft palate, intellectual disability and epilepsy (PMID: 17377962, 24301056). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg239*) 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). -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 21, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2024

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG: PVS1, PS4_Moderate, PM2_Supporting -

Dec 04, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 03, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PVS1, PS2, PS4_MOD, PS3_SUP, PM2_SUP -

not provided

Pathogenic:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate an abnormal truncated protein that forms a dimer with wild-type SATB2 and interferes with the activity of the wild-type protein suggesting a dominant-negative mechanism (Leoyklang et al., 2007; Leoyklang et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24363063, 31209962, 31144778, 23925499, 17377962, 25525159, 27774744, 28787087, 24301056, 30848049, 31021519) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cleft palate

Pathogenic:1

Jan 23, 2017

Autoinflammatory diseases unit, CHU de Montpellier

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Intellectual disability

Pathogenic:1

Apr 20, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SATB2-related disorder

Pathogenic:1

May 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SATB2 c.715C>T variant is predicted to result in premature protein termination (p.Arg239*). This variant has been reported in individuals with SATB2-associated syndrome (for example Leoyklang et al. 2007. PubMed ID: 17377962; Zarate et al. 2019. PubMedID: 31021519). Functional studies revealed that this variant produces a truncated protein that dimerizes with the wild-type protein to act in a dominant negative mechanism (Leoyklang et al. 2007. PubMed ID: 17377962; Leoyklang et al. 2013. PubMed ID: 23925499). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in SATB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

Vest4

0.97

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over