12-45852441-C-T

Variant names:

• chr12-45852441-C-T
• rs772995852
• NM_152641.4:c.4318C>T

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.4318C>T​(p.Gln1440*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARID2 NM_152641.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.43
• Publications: 4 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: Orphanet, Illumina, ClinGen
• Coffin-Siris syndrome 6

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

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 12-45852441-C-T is Pathogenic according to our data. Variant chr12-45852441-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 448918.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID2	NM_152641.4	MANE Select	c.4318C>T	p.Gln1440*	stop_gained	Exon 15 of 21	NP_689854.2
	ARID2	NM_001347839.2		c.4318C>T	p.Gln1440*	stop_gained	Exon 15 of 20	NP_001334768.1	F8WCU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID2	ENST00000334344.11	TSL:1 MANE Select	c.4318C>T	p.Gln1440*	stop_gained	Exon 15 of 21	ENSP00000335044.6	Q68CP9-1
	ARID2	ENST00000422737.7	TSL:1	c.4318C>T	p.Gln1440*	stop_gained	Exon 15 of 20	ENSP00000415650.3	F8WCU9
	ARID2	ENST00000444670.5	TSL:1	c.3163C>T	p.Gln1055*	stop_gained	Exon 7 of 13	ENSP00000397307.2	F8W108

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Coffin-Siris syndrome 6 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.4
Vest4		0.91
GERP RS		6.1
PromoterAI		-0.0042	Neutral
Mutation Taster		=2/198	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: rs772995852; hg19: chr12-46246224;