2-199349159-G-A

Position:

• chr2-199349159-G-A

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.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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 2.86

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 (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 2-199349159-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/exons	MANE	Protein	UniProt
SATB2	NM_001172509.2	c.715C>T	p.Arg239*	stop_gained	7/11	ENST00000417098.6	NP_001165980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SATB2	ENST00000417098.6	c.715C>T	p.Arg239*	stop_gained	7/11	2	NM_001172509.2	ENSP00000401112.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460450 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chromosome 2q32-q33 deletion syndrome Pathogenic:5 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 04, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Sep 20, 2024	ACMG: PVS1, PS4_Moderate, PM2_Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 03, 2022	_x000D_ Criteria applied: PVS1, PS2, PS4_MOD, PS3_SUP, PM2_SUP -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 09, 2022	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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with a clinical phenotype including cleft palate, intellectual disability and epilepsy (PMID: 17377962, 24301056). ClinVar contains an entry for this variant (Variation ID: 2519). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cleft palate Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Autoinflammatory diseases unit, CHU de Montpellier

Jan 23, 2017

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

SATB2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2024

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	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
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

Other links and lift over

dbSNP: rs137853127; hg19: chr2-200213882; COSMIC: COSV53482938;