Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001374828.1(ARID1B):c.1298_1300dupCAG(p.Ala433dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,280,972 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G434G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

ARID1B
NM_001374828.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 2.52

Publications

2 publications found

Variant links:

COSMIC-nc: COSV99034263

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

ARID1B links:

ENSG00000296922 (HGNC:):

ENSG00000296922 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001374828.1

BP6

Variant 6-156778970-G-GGCA is Benign according to our data. Variant chr6-156778970-G-GGCA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210265.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000572 (84/146770) while in subpopulation NFE AF = 0.00101 (67/66102). AF 95% confidence interval is 0.000818. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAd4 at 84 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARID1B	NM_001374828.1	MANE Select	c.1298_1300dupCAG	p.Ala433dup	disruptive_inframe_insertion	Exon 1 of 20	NP_001361757.1
ARID1B	NM_001438482.1		c.1298_1300dupCAG	p.Ala433dup	disruptive_inframe_insertion	Exon 1 of 21	NP_001425411.1
ARID1B	NM_001438483.1		c.1298_1300dupCAG	p.Ala433dup	disruptive_inframe_insertion	Exon 1 of 21	NP_001425412.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARID1B	ENST00000636930.2	TSL:2 MANE Select	c.1298_1300dupCAG	p.Ala433dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000490491.2
ARID1B	ENST00000346085.10	TSL:1	c.1298_1300dupCAG	p.Ala433dup	disruptive_inframe_insertion	Exon 2 of 21	ENSP00000344546.5
ARID1B	ENST00000350026.11	TSL:1	c.1298_1300dupCAG	p.Ala433dup	disruptive_inframe_insertion	Exon 1 of 19	ENSP00000055163.8

Frequencies

GnomAD3 genomes

AF:

0.000573

AC:

AN:

146666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000209

Gnomad SAS

AF:

0.000216

Gnomad FIN

AF:

0.000102

Gnomad MID

AF:

0.00350

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.000500

GnomAD2 exomes

AF:

0.000398

AC:

AN:

2514

AF XY:

0.00

show subpopulations

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:

0.00123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00113

AC:

1276

AN:

1134202

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

607

AN XY:

546376

show subpopulations

African (AFR)

AF:

0.000130

AC:

AN:

23042

American (AMR)

AF:

0.000116

AC:

AN:

8630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14728

East Asian (EAS)

AF:

0.0000746

AC:

AN:

26806

South Asian (SAS)

AF:

0.000181

AC:

AN:

27668

European-Finnish (FIN)

AF:

0.000346

AC:

AN:

26006

Middle Eastern (MID)

AF:

0.00379

AC:

AN:

3168

European-Non Finnish (NFE)

AF:

0.00126

AC:

1204

AN:

958284

Other (OTH)

AF:

0.000872

AC:

AN:

45870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000572

AC:

AN:

146770

Hom.:

Cov.:

AF XY:

0.000488

AC XY:

AN XY:

71778

show subpopulations

African (AFR)

AF:

0.000300

AC:

AN:

39966

American (AMR)

AF:

0.00

AC:

AN:

14946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.000210

AC:

AN:

4762

South Asian (SAS)

AF:

0.000216

AC:

AN:

4630

European-Finnish (FIN)

AF:

0.000102

AC:

AN:

9770

Middle Eastern (MID)

AF:

0.00373

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

66102

Other (OTH)

AF:

0.000495

AC:

AN:

2020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000552

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

ARID1B-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=78/22

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over