2-199272252-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS1_Supporting

The NM_001172509.2(SATB2):c.2161G>A(p.Asp721Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SATB2 NM_001172509.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SATB2
• BP4: Computational evidence support a benign effect (MetaRNN=0.1646738).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000342 (5/1461846) while in subpopulation MID AF= 0.00052 (3/5768). AF 95% confidence interval is 0.000141. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SATB2	NM_001172509.2	c.2161G>A	p.Asp721Asn	missense_variant	11/11	ENST00000417098.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SATB2	ENST00000417098.6	c.2161G>A	p.Asp721Asn	missense_variant	11/11	2	NM_001172509.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727226

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.2161G>A (p.D721N) alteration is located in exon 12 (coding exon 10) of the SATB2 gene. This alteration results from a G to A substitution at nucleotide position 2161, causing the aspartic acid (D) at amino acid position 721 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;T;T;.;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;N;.;N
MutationTaster	Benign	0.80	D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.84	N;.;N;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.049	D;.;T;D;D;D
Sift4G	Benign	0.85	T;T;T;T;T;T
Polyphen		0.0040	B;.;.;B;.;B
Vest4		0.11
MutPred		0.30		Loss of stability (P = 0.0308);.;.;Loss of stability (P = 0.0308);.;Loss of stability (P = 0.0308);
MVP		0.54
MPC		1.0
ClinPred		0.26	T
GERP RS		5.6
Varity_R		0.083
gMVP		0.095

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-200136975;