2-199368710-GAA-GA

Variant names:

• chr2-199368710-GA-G
• rs199978702
• NM_001172509.2:c.598-4delT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001172509.2(SATB2):​c.598-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,465,334 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: SATB2 NM_001172509.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.666
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• chromosome 2q32-q33 deletion syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• SATB2 associated disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 2-199368710-GA-G is Benign according to our data. Variant chr2-199368710-GA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 589489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172509.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SATB2	NM_001172509.2	MANE Select	c.598-4delT		splice_region intron	N/A	NP_001165980.1	Q9UPW6-1
	SATB2	NM_001172517.1		c.598-4delT		splice_region intron	N/A	NP_001165988.1	Q59FT3
	SATB2	NM_015265.4		c.598-4delT		splice_region intron	N/A	NP_056080.1	Q9UPW6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SATB2	ENST00000417098.6	TSL:2 MANE Select	c.598-4delT		splice_region intron	N/A	ENSP00000401112.1	Q9UPW6-1
	SATB2	ENST00000260926.9	TSL:1	c.598-4delT		splice_region intron	N/A	ENSP00000260926.5	Q9UPW6-1
	SATB2	ENST00000428695.6	TSL:1	c.347-19538delT		intron	N/A	ENSP00000388581.1	Q9UPW6-2

Frequencies

GnomAD3 genomes AF: 0.0000335 AC: 5 AN: 149146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000298

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000350 AC: 68 AN: 194282 AF XY: 0.000312

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.000388

Gnomad EAS exome AF: 0.000499

Gnomad FIN exome AF: 0.000558

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.000521 AC: 686 AN: 1316088 Hom.: 0 Cov.: 24 AF XY: 0.000494 AC XY: 325 AN XY: 658208

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000540 AC: 16 AN: 29616

American (AMR) AF: 0.000125 AC: 5 AN: 40032

Ashkenazi Jewish (ASJ) AF: 0.000251 AC: 6 AN: 23884

East Asian (EAS) AF: 0.0000824 AC: 3 AN: 36404

South Asian (SAS) AF: 0.000383 AC: 30 AN: 78266

European-Finnish (FIN) AF: 0.000304 AC: 15 AN: 49310

Middle Eastern (MID) AF: 0.000191 AC: 1 AN: 5248

European-Non Finnish (NFE) AF: 0.000590 AC: 589 AN: 998934

Other (OTH) AF: 0.000386 AC: 21 AN: 54394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000335 AC: 5 AN: 149246 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 4 AN XY: 72708

African (AFR) AF: 0.0000491 AC: 2 AN: 40766

American (AMR) AF: 0.00 AC: 0 AN: 14988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000298 AC: 2 AN: 67172

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00130 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Chromosome 2q32-q33 deletion syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199978702; hg19: chr2-200233433;