NM_001374828.1:c.2516_2518delCCGinsTCCGCAGCCACTCC

Variant names:

• chr6-157110496-CCG-TCCGCAGCCACTCC
• rs879253856
• NM_001374828.1:c.2516_2518delCCGinsTCCGCAGCCACTCC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001374828.1(ARID1B):​c.2516_2518delCCGinsTCCGCAGCCACTCC​(p.Pro839LeufsTer17) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P839P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARID1B NM_001374828.1 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.40
• Publications: 0 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

ENSG00000233044 (HGNC:40826):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-157110496-CCG-TCCGCAGCCACTCC is Pathogenic according to our data. Variant chr6-157110496-CCG-TCCGCAGCCACTCC is described in ClinVar as Pathogenic. ClinVar VariationId is 242865.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2516_2518delCCGinsTCCGCAGCCACTCC	p.Pro839LeufsTer17	frameshift missense	Exon 6 of 20	NP_001361757.1
	ARID1B	NM_001438482.1		c.2516_2518delCCGinsTCCGCAGCCACTCC	p.Pro839LeufsTer17	frameshift missense	Exon 6 of 21	NP_001425411.1
	ARID1B	NM_001438483.1		c.2558_2560delCCGinsTCCGCAGCCACTCC	p.Pro853LeufsTer17	frameshift missense	Exon 7 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.2516_2518delCCGinsTCCGCAGCCACTCC	p.Pro839LeufsTer17	frameshift missense	Exon 6 of 20	ENSP00000490491.2
	ARID1B	ENST00000346085.10	TSL:1	c.2555_2557delCCGinsTCCGCAGCCACTCC	p.Pro852LeufsTer17	frameshift missense	Exon 8 of 21	ENSP00000344546.5
	ARID1B	ENST00000350026.11	TSL:1	c.2516_2518delCCGinsTCCGCAGCCACTCC	p.Pro839LeufsTer17	frameshift missense	Exon 6 of 19	ENSP00000055163.8

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Blepharophimosis;C0026351:Intellectual disability, moderate;C1839739:Thick lower lip vermilion;C1853738:Long eyelashes;C1854882:Absent speech;C1865017:Thin upper lip vermilion Pathogenic:1

Mar 27, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.4
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs879253856; hg19: chr6-157431630;