chr2-199308957-C-T

Position:

• chr2-199308957-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

The NM_001172509.2(SATB2):​c.1543G>A​(p.Gly515Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G515D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SATB2 NM_001172509.2 missense, splice_region
• Scores: Splicing: ADA: 0.9983
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.82

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 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 chr2-199308956-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1338898.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SATB2. . Gene score misZ 4.0511 (greater than the threshold 3.09). Trascript score misZ 5.5168 (greater than threshold 3.09). GenCC has associacion of gene with chromosome 2q32-q33 deletion syndrome, SATB2 associated disorder.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-199308957-C-T is Pathogenic according to our data. Variant chr2-199308957-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 545530.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-199308957-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SATB2	NM_001172509.2	c.1543G>A	p.Gly515Ser	missense_variant, splice_region_variant	10/11	ENST00000417098.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SATB2	ENST00000417098.6	c.1543G>A	p.Gly515Ser	missense_variant, splice_region_variant	10/11	2	NM_001172509.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Chromosome 2q32-q33 deletion syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 12, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;T;T;.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;D;.;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.9	L;.;.;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;.;D;D;D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;.;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;D
Vest4		0.93
MutPred		0.79		Gain of helix (P = 0.0696);.;.;Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);
MVP		0.82
MPC		2.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.12		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: rs1553544187; hg19: chr2-200173680; COSMIC: COSV53480124;