rs1553547838

chr2-199328709-G-Achr2-199328709-G-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.1375C>T(p.Arg459Ter) variant causes a stop gained change. 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:11 O:1
• Conservation: PhyloP100: 4.86

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]

(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 2-199328709-G-A is Pathogenic according to our data. Variant chr2-199328709-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 522269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-199328709-G-A is described in Lovd as [Pathogenic]. Variant chr2-199328709-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-199328709-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SATB2	NM_001172509.2	c.1375C>T	p.Arg459Ter	stop_gained	8/11	ENST00000417098.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SATB2	ENST00000417098.6	c.1375C>T	p.Arg459Ter	stop_gained	8/11	2	NM_001172509.2	P1
	ENST00000489557.2	n.258-80G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chromosome 2q32-q33 deletion syndrome Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in a set of 10-year-old male twins with intellectual disability, dysmorphisms, cleft palate, hyperextensibility -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 25533962, 28151491). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change creates a premature translational stop signal (p.Arg459*) 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 Glass syndrome (PMID: 26596517, 28211976). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522269). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2023	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28211976, 32446642, 25533962, 28135719, 29436146, 28191890, 26596517, 25326635, 32581362, 31785789) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Isolated cleft palate Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 24, 2014	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2017

The p.R459* pathogenic mutation (also known as c.1375C>T), located in coding exon 7 of the SATB2 gene, results from a C to T substitution at nucleotide position 1375. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation occurred de novo in two patients with developmental delay and cleft palate (Deciphering Developmental Disorders Study. Nature, 2015 Mar;519:223-8; Lee JS et al. Clin. Genet., 2016 Jun;89:728-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Aug 29, 2022

- -

Dystonic disorder;C3714756:Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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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	0.85
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.91
GERP RS		3.9

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: rs1553547838; hg19: chr2-200193432;