rs796052240

chr12-45850658-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152641.4(ARID2):c.2536del(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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 207823.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-45850658-TG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID2	NM_152641.4	c.2536del	p.Val846LeufsTer3	frameshift_variant	15/21	ENST00000334344.11
ARID2	NM_001347839.2	c.2536del	p.Val846LeufsTer3	frameshift_variant	15/20
ARID2	XM_047428489.1	c.2536del	p.Val846LeufsTer3	frameshift_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID2	ENST00000334344.11	c.2536del	p.Val846LeufsTer3	frameshift_variant	15/21	1	NM_152641.4	P1
ARID2	ENST00000422737.7	c.2536del	p.Val846LeufsTer3	frameshift_variant	15/20	1
ARID2	ENST00000444670.5	c.1382del	p.Val462LeufsTer3	frameshift_variant	7/13	1
ARID2	ENST00000479608.5	c.*1086del		3_prime_UTR_variant, NMD_transcript_variant	9/15	1

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 12, 2016

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs796052240; hg19: chr12-46244441;