12-45730131-C-G

Variant names:

• chr12-45730131-C-G
• rs200775326
• NM_152641.4:c.180C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152641.4(ARID2):​c.180C>G​(p.Phe60Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,378 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F60F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARID2 NM_152641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.814
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.180C>G	p.Phe60Leu	missense	Exon 2 of 21	NP_689854.2
	ARID2	NM_001347839.2		c.180C>G	p.Phe60Leu	missense	Exon 2 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.180C>G	p.Phe60Leu	missense	Exon 2 of 21	ENSP00000335044.6	Q68CP9-1
	ARID2	ENST00000422737.7	TSL:1	c.180C>G	p.Phe60Leu	missense	Exon 2 of 20	ENSP00000415650.3	F8WCU9
	ARID2	ENST00000851072.1		c.180C>G	p.Phe60Leu	missense	Exon 2 of 21	ENSP00000521133.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460378 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726524

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.0000224 AC: 1 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111144

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.048
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.81
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.38
Sift	Benign	0.13	T
Sift4G	Uncertain	0.044	D
Polyphen		0.99	D
Vest4		0.37
MutPred		0.76		Gain of catalytic residue at T56 (P = 0.0176)
MVP		0.47
MPC		1.2
ClinPred		0.78	D
GERP RS		1.9
PromoterAI		0.0010	Neutral
Varity_R		0.19
gMVP		0.76
Mutation Taster		=53/47	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: rs200775326; hg19: chr12-46123914;