2-199368710-GAA-GAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001172509.2(SATB2):​c.598-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,438,694 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (0 hom.)
• Consequence: SATB2 NM_001172509.2 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 2-199368710-G-GA is Benign according to our data. Variant chr2-199368710-G-GA is described in ClinVar as Benign. ClinVar VariationId is 469562.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000322 (48/149220) while in subpopulation AMR AF = 0.000534 (8/14988). AF 95% confidence interval is 0.000347. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 48 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.598-4dupT		splice_region intron	N/A	NP_001165980.1	Q9UPW6-1
	SATB2	NM_001172517.1		c.598-4dupT		splice_region intron	N/A	NP_001165988.1	Q59FT3
	SATB2	NM_015265.4		c.598-4dupT		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.598-4dupT		splice_region intron	N/A	ENSP00000401112.1	Q9UPW6-1
	SATB2	ENST00000260926.9	TSL:1	c.598-4dupT		splice_region intron	N/A	ENSP00000260926.5	Q9UPW6-1
	SATB2	ENST00000428695.6	TSL:1	c.347-19538dupT		intron	N/A	ENSP00000388581.1	Q9UPW6-2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 48 AN: 149120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000738

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000534

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000476

Gnomad OTH AF: 0.00246

GnomAD2 exomes AF: 0.00214 AC: 416 AN: 194282 AF XY: 0.00221

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.00207

Gnomad EAS exome AF: 0.000927

Gnomad FIN exome AF: 0.00354

Gnomad NFE exome AF: 0.00216

Gnomad OTH exome AF: 0.00307

GnomAD4 exome AF: 0.00615 AC: 7926 AN: 1289474 Hom.: 0 Cov.: 24 AF XY: 0.00579 AC XY: 3730 AN XY: 644658

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

African (AFR) AF: 0.00517 AC: 150 AN: 29016

American (AMR) AF: 0.00256 AC: 100 AN: 39092

Ashkenazi Jewish (ASJ) AF: 0.00357 AC: 83 AN: 23256

East Asian (EAS) AF: 0.00274 AC: 97 AN: 35346

South Asian (SAS) AF: 0.00257 AC: 197 AN: 76732

European-Finnish (FIN) AF: 0.00291 AC: 140 AN: 48100

Middle Eastern (MID) AF: 0.00578 AC: 30 AN: 5186

European-Non Finnish (NFE) AF: 0.00695 AC: 6804 AN: 979630

Other (OTH) AF: 0.00612 AC: 325 AN: 53116

⚠️ 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: 0.000322 AC: 48 AN: 149220 Hom.: 0 Cov.: 32 AF XY: 0.000344 AC XY: 25 AN XY: 72694

African (AFR) AF: 0.0000736 AC: 3 AN: 40760

American (AMR) AF: 0.000534 AC: 8 AN: 14988

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9774

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

European-Non Finnish (NFE) AF: 0.000476 AC: 32 AN: 67160

Other (OTH) AF: 0.00243 AC: 5 AN: 2058

Alfa AF: 0.0106 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs199978702; hg19: chr2-200233433; COSMIC: COSV104368542;