2-74457608-T-G

Variant names:

• chr2-74457608-T-G
• rs747445939
• NM_031288.4:c.815T>G

Variant summary

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

The NM_031288.4(INO80B):​c.815T>G​(p.Met272Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,564,422 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M272L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: INO80B NM_031288.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52
• Publications: 0 publications found

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-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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031288.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INO80B	NM_031288.4	MANE Select	c.815T>G	p.Met272Arg	missense	Exon 5 of 5	NP_112578.2	Q9C086
	INO80B-WBP1	NR_037849.1		n.909T>G		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INO80B	ENST00000233331.12	TSL:1 MANE Select	c.815T>G	p.Met272Arg	missense	Exon 5 of 5	ENSP00000233331.7	Q9C086
	INO80B-WBP1	ENST00000452361.5	TSL:2	n.815T>G		non_coding_transcript_exon	Exon 5 of 8	ENSP00000388677.1	J3KQ70
	INO80B	ENST00000409917.5	TSL:2	c.*172T>G		3_prime_UTR	Exon 5 of 5	ENSP00000387267.1	B8ZZ93

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 173768 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: 0.0000135 AC: 19 AN: 1412326 Hom.: 0 Cov.: 33 AF XY: 0.0000129 AC XY: 9 AN XY: 700146

African (AFR) AF: 0.00 AC: 0 AN: 31526

American (AMR) AF: 0.00 AC: 0 AN: 39670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24868

East Asian (EAS) AF: 0.00 AC: 0 AN: 37238

South Asian (SAS) AF: 0.00 AC: 0 AN: 82016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4614

European-Non Finnish (NFE) AF: 0.0000174 AC: 19 AN: 1093582

Other (OTH) AF: 0.00 AC: 0 AN: 58576

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

African (AFR) AF: 0.0000242 AC: 1 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000854 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.30
Sift	Benign	0.28	T
Sift4G	Benign	0.44	T
Polyphen		0.26	B
Vest4		0.79
MutPred		0.52		Gain of sheet (P = 0.0221)
MVP		0.75
MPC		1.3
ClinPred		0.77	D
GERP RS		3.2
Varity_R		0.92
gMVP		0.78
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs747445939; hg19: chr2-74684735;