12-45852346-A-T

Variant names:

• chr12-45852346-A-T
• rs374602869
• NM_152641.4:c.4223A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152641.4(ARID2):​c.4223A>T​(p.Lys1408Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1408R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARID2 NM_152641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.70
• 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: Illumina, Orphanet, ClinGen
• Coffin-Siris syndrome 6

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40285572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARID2	NM_152641.4	c.4223A>T	p.Lys1408Ile	missense_variant	Exon 15 of 21	ENST00000334344.11	NP_689854.2
ARID2	NM_001347839.2	c.4223A>T	p.Lys1408Ile	missense_variant	Exon 15 of 20		NP_001334768.1
ARID2	XM_047428489.1	c.4223A>T	p.Lys1408Ile	missense_variant	Exon 15 of 17		XP_047284445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARID2	ENST00000334344.11	c.4223A>T	p.Lys1408Ile	missense_variant	Exon 15 of 21	1	NM_152641.4	ENSP00000335044.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.0	L;.;.;.
PhyloP100		6.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.70
MutPred		0.29		Gain of catalytic residue at L1412 (P = 1e-04);.;.;.;
MVP		0.59
MPC		0.77
ClinPred		0.80	D
GERP RS		6.1
PromoterAI		-0.0037	Neutral
Varity_R		0.55
gMVP		0.47
Mutation Taster		=42/58	disease causing

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: rs374602869; hg19: chr12-46246129;