12-45849672-C-G

Position:

• chr12-45849672-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BS1_Supporting

The NM_152641.4(ARID2):​c.1808C>G​(p.Ala603Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A603V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARID2 NM_152641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30

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]

LOC105369745 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ARID2
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000205 (3/1461574) while in subpopulation AMR AF= 0.0000671 (3/44720). AF 95% confidence interval is 0.0000178. There are 0 homozygotes in gnomad4_exome. There are 0 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID2	NM_152641.4	c.1808C>G	p.Ala603Gly	missense_variant	14/21	ENST00000334344.11
ARID2	NM_001347839.2	c.1808C>G	p.Ala603Gly	missense_variant	14/20
ARID2	XM_047428489.1	c.1808C>G	p.Ala603Gly	missense_variant	14/17
LOC105369745	XR_944892.3			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID2	ENST00000334344.11	c.1808C>G	p.Ala603Gly	missense_variant	14/21	1	NM_152641.4	P1
ARID2	ENST00000422737.7	c.1808C>G	p.Ala603Gly	missense_variant	14/20	1
ARID2	ENST00000444670.5	c.656C>G	p.Ala219Gly	missense_variant	6/13	1
ARID2	ENST00000479608.5	c.*358C>G		3_prime_UTR_variant, NMD_transcript_variant	8/15	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251240 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461574 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2024

The c.1808C>G (p.A603G) alteration is located in exon 14 (coding exon 14) of the ARID2 gene. This alteration results from a C to G substitution at nucleotide position 1808, causing the alanine (A) at amino acid position 603 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0020	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.018	D;D;D
Sift4G	Benign	0.083	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.68
MutPred		0.43		Gain of catalytic residue at L606 (P = 0);.;.;
MVP		0.45
MPC		0.45
ClinPred		0.79	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144928351; hg19: chr12-46243455;