NM_006015.6:c.492_494dupCGC

Variant names:

• chr1-26696885-T-TCGC
• rs759913677
• NM_006015.6:c.492_494dupCGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_006015.6(ARID1A):​c.492_494dupCGC​(p.Ala165dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,348,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A165A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: ARID1A NM_006015.6 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.849
• Publications: 1 publications found

Genes affected

ARID1A (HGNC:11110): (AT-rich interaction domain 1A) This gene encodes a member of the SWI/SNF family, whose members have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. It possesses at least two conserved domains that could be important for its function. First, it has a DNA-binding domain that can specifically bind an AT-rich DNA sequence known to be recognized by a SNF/SWI complex at the beta-globin locus. Second, the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. It is thought that the protein encoded by this gene confers specificity to the SNF/SWI complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ARID1A Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, autosomal dominant 14

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006015.6. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 1-26696885-T-TCGC is Benign according to our data. Variant chr1-26696885-T-TCGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434333.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000763 (917/1202620) while in subpopulation NFE AF = 0.000877 (864/985420). AF 95% confidence interval is 0.000828. There are 0 homozygotes in GnomAdExome4. There are 402 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAd4 at 62 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006015.6. 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
	ARID1A	NM_006015.6	MANE Select	c.492_494dupCGC	p.Ala165dup	disruptive_inframe_insertion	Exon 1 of 20	NP_006006.3
	ARID1A	NM_139135.4		c.492_494dupCGC	p.Ala165dup	disruptive_inframe_insertion	Exon 1 of 20	NP_624361.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARID1A	ENST00000324856.13	TSL:1 MANE Select	c.492_494dupCGC	p.Ala165dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000320485.7
	ARID1A	ENST00000850904.1		c.492_494dupCGC	p.Ala165dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000520984.1
	ARID1A	ENST00000457599.7	TSL:5	c.492_494dupCGC	p.Ala165dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000387636.2

Frequencies

GnomAD3 genomes AF: 0.000425 AC: 62 AN: 145868 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.00115

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: 0.000710

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000839 AC: 2 AN: 23828 AF XY: 0.0000758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000763 AC: 917 AN: 1202620 Hom.: 0 Cov.: 35 AF XY: 0.000689 AC XY: 402 AN XY: 583278

African (AFR) AF: 0.000293 AC: 7 AN: 23872

American (AMR) AF: 0.00 AC: 0 AN: 9544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15920

East Asian (EAS) AF: 0.00 AC: 0 AN: 27428

South Asian (SAS) AF: 0.00 AC: 0 AN: 47436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4700

European-Non Finnish (NFE) AF: 0.000877 AC: 864 AN: 985420

Other (OTH) AF: 0.000953 AC: 46 AN: 48288

GnomAD4 genome AF: 0.000425 AC: 62 AN: 146000 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 23 AN XY: 71308

African (AFR) AF: 0.000356 AC: 14 AN: 39370

American (AMR) AF: 0.00 AC: 0 AN: 14910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 4478

South Asian (SAS) AF: 0.00 AC: 0 AN: 4372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.000710 AC: 47 AN: 66152

Other (OTH) AF: 0.00 AC: 0 AN: 2036

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000355

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Sep 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Mar 04, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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.

ARID1A-related disorder Benign:1

Sep 27, 2023

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).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85
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: rs759913677; hg19: chr1-27023376; COSMIC: COSV99081675;