Genetic Variant NM_031288.4:c.677A>T (chr2-74457470-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031288.4(INO80B):c.677A>T(p.Gln226Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,318 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

INO80B
NM_031288.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.50

Publications

0 publications found

Variant links:

Genes affected

INO80B (HGNC:13324): (INO80 complex subunit B) This gene encodes a subunit of an ATP-dependent chromatin remodeling complex, INO80, which plays a role in DNA and nucleosome-activated ATPase activity and ATP-dependent nucleosome sliding. Readthrough transcription of this gene into the neighboring downstream gene, which encodes WW domain-binding protein 1, generates a non-coding transcript. [provided by RefSeq, Feb 2011]

INO80B links:

INO80B-WBP1 (HGNC:49199): (INO80B-WBP1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring INO80B (INO80 complex subunit B) and WBP1 (WW domain-binding protein 1) genes on chromosome 2. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

INO80B-WBP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INO80B	NM_031288.4 link	c.677A>T	p.Gln226Leu	missense_variant	Exon 5 of 5	ENST00000233331.12	NP_112578.2	Q9C086
INO80B-WBP1	NR_037849.1 link	n.771A>T		non_coding_transcript_exon_variant	Exon 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INO80B	ENST00000233331.12 link	c.677A>T	p.Gln226Leu	missense_variant	Exon 5 of 5	1	NM_031288.4	ENSP00000233331.7		Q9C086
INO80B-WBP1	ENST00000452361.5 link	n.677A>T		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000388677.1		J3KQ70

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

158108

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1406318

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694902

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31924

American (AMR)

AF:

0.00

AC:

AN:

36896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.00

AC:

AN:

36290

South Asian (SAS)

AF:

0.00

AC:

AN:

80278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

9.23e-7

AC:

AN:

1083796

Other (OTH)

AF:

0.00

AC:

AN:

58298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.677A>T (p.Q226L) alteration is located in exon 5 (coding exon 5) of the INO80B gene. This alteration results from a A to T substitution at nucleotide position 677, causing the glutamine (Q) at amino acid position 226 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

0.0060

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.6

PhyloP100

8.5

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.35

Sift

Benign

0.13

Sift4G

Benign

1.0

Polyphen

0.99

Vest4

0.62

MutPred

0.49

Gain of methylation at K222 (P = 0.2185);

MVP

0.20

MPC

1.6

ClinPred

0.99

GERP RS

4.6

Varity_R

0.42

gMVP

0.73

Mutation Taster

=49/51

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over