6-156778982-AGGCGGCGGC-AGGCGGCGGCGGC

Position:

• chr6-156778982-AGGCGGCGGC-AGGCGGCGGCGGC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_001374828.1(ARID1B):​c.1318_1320dup​(p.Gly440dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000928 in 1,262,816 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00078 (2 hom.)
• Consequence: ARID1B NM_001374828.1 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001374828.1
• BP6: Variant 6-156778982-A-AGGC is Benign according to our data. Variant chr6-156778982-A-AGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434377.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0021 (289/137404) while in subpopulation AFR AF= 0.00599 (220/36758). AF 95% confidence interval is 0.00534. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 289 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARID1B	NM_001374828.1	c.1318_1320dup	p.Gly440dup	inframe_insertion	1/20	ENST00000636930.2	NP_001361757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARID1B	ENST00000636930.2	c.1318_1320dup	p.Gly440dup	inframe_insertion	1/20	2	NM_001374828.1	ENSP00000490491	A2

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 289 AN: 137298 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00600

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00168

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000240

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000653

Gnomad OTH AF: 0.00160

GnomAD4 exome AF: 0.000785 AC: 883 AN: 1125412 Hom.: 2 Cov.: 35 AF XY: 0.000731 AC XY: 396 AN XY: 541864

Gnomad4 AFR exome AF: 0.00499

Gnomad4 AMR exome AF: 0.000714

Gnomad4 ASJ exome AF: 0.000415

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.0000405

Gnomad4 NFE exome AF: 0.000712

Gnomad4 OTH exome AF: 0.00135

GnomAD4 genome AF: 0.00210 AC: 289 AN: 137404 Hom.: 0 Cov.: 29 AF XY: 0.00168 AC XY: 113 AN XY: 67290

Gnomad4 AFR AF: 0.00599

Gnomad4 AMR AF: 0.00168

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000240

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000653

Gnomad4 OTH AF: 0.00158

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ARID1B: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 13, 2016

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2019

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. -

ARID1B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045268; hg19: chr6-157100116;