chr12-45850658-TG-T

Variant names:

• chr12-45850658-TG-T
• rs796052240
• NM_152641.4:c.2536delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152641.4(ARID2):​c.2536delG​(p.Val846LeufsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARID2 NM_152641.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.13
• Publications: 3 publications found

Genes affected

ARID2 (HGNC:18037): (AT-rich interaction domain 2) This gene encodes a member of the AT-rich interactive domain (ARID)-containing family of DNA-binding proteins. Members of the ARID family have roles in embryonic patterning, cell lineage gene regulation, cell cycle control, transcriptional regulation and chromatin structure modification. This protein functions as a subunit of the polybromo- and BRG1-associated factor or PBAF (SWI/SNF-B) chromatin remodeling complex which facilitates ligand-dependent transcriptional activation by nuclear receptors. Mutations in this gene are associated with hepatocellular carcinomas. A pseudogene of this gene is found on chromosome1. [provided by RefSeq, Dec 2016]

ARID2 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, ClinGen
• Coffin-Siris syndrome 6

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-45850658-TG-T is Pathogenic according to our data. Variant chr12-45850658-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 207823.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152641.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID2	NM_152641.4	MANE Select	c.2536delG	p.Val846LeufsTer3	frameshift	Exon 15 of 21	NP_689854.2
	ARID2	NM_001347839.2		c.2536delG	p.Val846LeufsTer3	frameshift	Exon 15 of 20	NP_001334768.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID2	ENST00000334344.11	TSL:1 MANE Select	c.2536delG	p.Val846LeufsTer3	frameshift	Exon 15 of 21	ENSP00000335044.6
	ARID2	ENST00000422737.7	TSL:1	c.2536delG	p.Val846LeufsTer3	frameshift	Exon 15 of 20	ENSP00000415650.3
	ARID2	ENST00000444670.5	TSL:1	c.1381delG	p.Val461fs	frameshift	Exon 7 of 13	ENSP00000397307.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 12, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2536delG pathogenic variant in the ARID2 gene has now been published as a disease-causing variant associated with ARID2-related disorders (Shang et al., 2015). The c.2536delG variant causes a frameshift starting with codon Valine 846, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Val846LeufsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2536delG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2536delG as a pathogenic variant

Coffin-Siris syndrome 6 Pathogenic:1

Dec 14, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs796052240; hg19: chr12-46244441;