rs78712333

chr12-45852828-G-Achr12-45852828-G-Cchr12-45852828-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152641.4(ARID2):c.4705G>A(p.Ala1569Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,696 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: ARID2 NM_152641.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 9.56

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ARID2
• BP4: Computational evidence support a benign effect (MetaRNN=0.00883469).
• BP6: Variant 12-45852828-G-A is Benign according to our data. Variant chr12-45852828-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 133571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00128 (195/152342) while in subpopulation NFE AF= 0.00151 (103/68034). AF 95% confidence interval is 0.00128. There are 1 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 195 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARID2	NM_152641.4	c.4705G>A	p.Ala1569Thr	missense_variant	15/21	ENST00000334344.11
ARID2	NM_001347839.2	c.4705G>A	p.Ala1569Thr	missense_variant	15/20
ARID2	XM_047428489.1	c.4705G>A	p.Ala1569Thr	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARID2	ENST00000334344.11	c.4705G>A	p.Ala1569Thr	missense_variant	15/21	1	NM_152641.4	P1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00192 AC: 477 AN: 247994 Hom.: 2 AF XY: 0.00191 AC XY: 257 AN XY: 134384

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.0248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00151 AC: 2213 AN: 1461354 Hom.: 5 Cov.: 32 AF XY: 0.00156 AC XY: 1137 AN XY: 726936

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00115 AC XY: 86 AN XY: 74500

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.0181

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00250 Hom.: 4

Bravo AF: 0.00139

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00151 AC: 183

EpiCase AF: 0.00224

EpiControl AF: 0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ARID2: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

ARID2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.060	T;T;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0088	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.0	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.72	N;N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.17	T;T;T;D
Polyphen		1.0	D;.;D;.
Vest4		0.71
MVP		0.70
MPC		0.57
ClinPred		0.047	T
GERP RS		5.9
Varity_R		0.27
gMVP		0.59

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: rs78712333; hg19: chr12-46246611; COSMIC: COSV100536536;