6-156778906-GAGGAGGAGCAGGAGC-GAGGAGGAGCAGGAGCAGGAGGAGCAGGAGC

Variant names:

• chr6-156778906-G-GAGGAGGAGCAGGAGC
• rs773423003
• NM_001374828.1:c.1242_1256dupAGGAGGAGCAGGAGC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BS2_Supporting

The NM_001374828.1(ARID1B):​c.1242_1256dupAGGAGGAGCAGGAGC​(p.Ala419_Gly420insGlyGlyAlaGlyAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000337 in 148,332 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARID1B NM_001374828.1 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.907
• Publications: 4 publications found

Genes affected

ARID1B (HGNC:18040): (AT-rich interaction domain 1B) This locus encodes an AT-rich DNA interacting domain-containing protein. The encoded protein is a component of the SWI/SNF chromatin remodeling complex and may play a role in cell-cycle activation. The protein encoded by this locus is similar to AT-rich interactive domain-containing protein 1A. These two proteins function as alternative, mutually exclusive ARID-subunits of the SWI/SNF complex. The associated complexes play opposing roles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ARID1B Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina, ClinGen
• Coffin-Siris syndrome 1

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

ENSG00000296922 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001374828.1
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374828.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1B	NM_001374828.1	MANE Select	c.1242_1256dupAGGAGGAGCAGGAGC	p.Ala419_Gly420insGlyGlyAlaGlyAla	disruptive_inframe_insertion	Exon 1 of 20	NP_001361757.1
	ARID1B	NM_001438482.1		c.1242_1256dupAGGAGGAGCAGGAGC	p.Ala419_Gly420insGlyGlyAlaGlyAla	disruptive_inframe_insertion	Exon 1 of 21	NP_001425411.1
	ARID1B	NM_001438483.1		c.1242_1256dupAGGAGGAGCAGGAGC	p.Ala419_Gly420insGlyGlyAlaGlyAla	disruptive_inframe_insertion	Exon 1 of 21	NP_001425412.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1B	ENST00000636930.2	TSL:2 MANE Select	c.1242_1256dupAGGAGGAGCAGGAGC	p.Ala419_Gly420insGlyGlyAlaGlyAla	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000490491.2
	ARID1B	ENST00000346085.10	TSL:1	c.1242_1256dupAGGAGGAGCAGGAGC	p.Ala419_Gly420insGlyGlyAlaGlyAla	disruptive_inframe_insertion	Exon 2 of 21	ENSP00000344546.5
	ARID1B	ENST00000350026.11	TSL:1	c.1242_1256dupAGGAGGAGCAGGAGC	p.Ala419_Gly420insGlyGlyAlaGlyAla	disruptive_inframe_insertion	Exon 1 of 19	ENSP00000055163.8

Frequencies

GnomAD3 genomes AF: 0.0000337 AC: 5 AN: 148228 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000287 AC: 35 AN: 1218794 Hom.: 0 Cov.: 35 AF XY: 0.0000386 AC XY: 23 AN XY: 595788

African (AFR) AF: 0.0000837 AC: 2 AN: 23888

American (AMR) AF: 0.00 AC: 0 AN: 12154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17798

East Asian (EAS) AF: 0.000109 AC: 3 AN: 27498

South Asian (SAS) AF: 0.0000403 AC: 2 AN: 49630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4138

European-Non Finnish (NFE) AF: 0.0000271 AC: 27 AN: 995488

Other (OTH) AF: 0.0000203 AC: 1 AN: 49320

GnomAD4 genome AF: 0.0000337 AC: 5 AN: 148332 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 1 AN XY: 72490

African (AFR) AF: 0.000123 AC: 5 AN: 40544

American (AMR) AF: 0.00 AC: 0 AN: 15012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 4816

South Asian (SAS) AF: 0.00 AC: 0 AN: 4688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66692

Other (OTH) AF: 0.00 AC: 0 AN: 2056

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.91
Mutation Taster		=79/21	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773423003; hg19: chr6-157100040;