chr2-161423752-C-CGCTGCAG

Variant names:

• chr2-161423752-C-CGCTGCAG
• rs869312704
• NM_006593.4:c.1588_1594dupGGCTGCA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006593.4(TBR1):​c.1588_1594dupGGCTGCA​(p.Thr532ArgfsTer144) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBR1 NM_006593.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: -1.77
• Publications: 4 publications found

Genes affected

TBR1 (HGNC:11590): (T-box brain transcription factor 1) This gene is a member of a conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of numerous developmental processes. In mouse, the ortholog of this gene is expressed in the cerebral cortex, hippocampus, amygdala and olfactory bulb and is thought to play an important role in neuronal migration and axonal projection. In mouse, the C-terminal region of this protein was found to be necessary and sufficient for association with the guanylate kinase domain of calcium/calmodulin-dependent serine protein kinase. [provided by RefSeq, Dec 2015]

TBR1 Gene-Disease associations (from GenCC):

• autism

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with autism and speech delay

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• occipital pachygyria and polymicrogyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000224076 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-161423752-C-CGCTGCAG is Pathogenic according to our data. Variant chr2-161423752-C-CGCTGCAG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006593.4. 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
	TBR1	NM_006593.4	MANE Select	c.1588_1594dupGGCTGCA	p.Thr532ArgfsTer144	frameshift	Exon 6 of 6	NP_006584.1	Q16650-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBR1	ENST00000389554.8	TSL:1 MANE Select	c.1588_1594dupGGCTGCA	p.Thr532ArgfsTer144	frameshift	Exon 6 of 6	ENSP00000374205.3	Q16650-1
	TBR1	ENST00000410035.1	TSL:2	c.727_733dupGGCTGCA	p.Thr245ArgfsTer144	frameshift	Exon 5 of 5	ENSP00000387023.1	Q16650-2
	TBR1	ENST00000411412.5	TSL:5	c.688_694dupGGCTGCA	p.Thr232ArgfsTer4	frameshift	Exon 6 of 6	ENSP00000393934.1	H7C0B1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Intellectual developmental disorder with autism and speech delay (7)
4	-	-	not provided (4)
1	-	-	Autistic behavior (1)
1	-	-	Autistic behavior;C1837397:Severe global developmental delay (1)
1	-	-	Autistic behavior;C1837397:Severe global developmental delay;C4022749:Abnormal brainstem MRI signal intensity;C4023681:Delayed fine motor development (1)
1	-	-	Autistic behavior;C2237142:Moderate global developmental delay (1)
1	-	-	Gait ataxia;C1837397:Severe global developmental delay;C1849172:Hypoplasia of the frontal lobes;C4023681:Delayed fine motor development (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (1)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	Seizure;C0751837:Gait ataxia;C1837397:Severe global developmental delay;C2938983:Focal cortical dysplasia;C4023681:Delayed fine motor development (1)
1	-	-	Severe global developmental delay (1)
-	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.8
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs869312704; hg19: chr2-162280263;