6-156778292-ACAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAG

Variant names:

• chr6-156778292-ACAG-A
• rs587779744
• NM_001374828.1:c.633_635delGCA

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_001374828.1(ARID1B):​c.633_635delGCA​(p.Gln212del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,485,114 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q211Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: ARID1B NM_001374828.1 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.46
• Publications: 12 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

ENSG00000271551 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001374828.1
• BP6: Variant 6-156778292-ACAG-A is Benign according to our data. Variant chr6-156778292-ACAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 13 AD gene.

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.633_635delGCA	p.Gln212del	disruptive_inframe_deletion	Exon 1 of 20	NP_001361757.1
	ARID1B	NM_001438482.1		c.633_635delGCA	p.Gln212del	disruptive_inframe_deletion	Exon 1 of 21	NP_001425411.1
	ARID1B	NM_001438483.1		c.633_635delGCA	p.Gln212del	disruptive_inframe_deletion	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.633_635delGCA	p.Gln212del	disruptive_inframe_deletion	Exon 1 of 20	ENSP00000490491.2
	ARID1B	ENST00000346085.10	TSL:1	c.633_635delGCA	p.Gln212del	disruptive_inframe_deletion	Exon 2 of 21	ENSP00000344546.5
	ARID1B	ENST00000350026.11	TSL:1	c.633_635delGCA	p.Gln212del	disruptive_inframe_deletion	Exon 1 of 19	ENSP00000055163.8

Frequencies

GnomAD3 genomes AF: 0.0000826 AC: 12 AN: 145268 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000826

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.0000958

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000744

Gnomad OTH AF: 0.000501

GnomAD2 exomes AF: 0.000886 AC: 112 AN: 126374 AF XY: 0.000884

Gnomad AFR exome AF: 0.000502

Gnomad AMR exome AF: 0.0000444

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000212

Gnomad FIN exome AF: 0.00778

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.000266

GnomAD4 exome AF: 0.000223 AC: 299 AN: 1339746 Hom.: 1 AF XY: 0.000230 AC XY: 152 AN XY: 661042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000736 AC: 2 AN: 27180

American (AMR) AF: 0.0000589 AC: 2 AN: 33962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24212

East Asian (EAS) AF: 0.000119 AC: 4 AN: 33696

South Asian (SAS) AF: 0.000610 AC: 46 AN: 75394

European-Finnish (FIN) AF: 0.00277 AC: 115 AN: 41464

Middle Eastern (MID) AF: 0.000185 AC: 1 AN: 5410

European-Non Finnish (NFE) AF: 0.000116 AC: 121 AN: 1043140

Other (OTH) AF: 0.000145 AC: 8 AN: 55288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000894 AC: 13 AN: 145368 Hom.: 0 Cov.: 31 AF XY: 0.0000844 AC XY: 6 AN XY: 71126

African (AFR) AF: 0.0000823 AC: 3 AN: 36446

American (AMR) AF: 0.00 AC: 0 AN: 14984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4942

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4770

European-Finnish (FIN) AF: 0.0000958 AC: 1 AN: 10440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000745 AC: 5 AN: 67158

Other (OTH) AF: 0.000990 AC: 2 AN: 2020

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 15, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ARID1B-related disorder Benign:1

Mar 02, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Inborn genetic diseases Benign:1

Dec 27, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not provided Benign:1

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=79/21	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: rs587779744; hg19: chr6-157099426; COSMIC: COSV51652090; COSMIC: COSV51652090;