Genetic Variant NM_012228.4:c.74C>T (chr10-23095682-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012228.4(MSRB2):c.74C>T(p.Ala25Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,168,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A25E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MSRB2
NM_012228.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.483

Publications

0 publications found

Variant links:

Genes affected

MSRB2 (HGNC:17061): (methionine sulfoxide reductase B2) Predicted to enable actin binding activity; peptide-methionine (R)-S-oxide reductase activity; and zinc ion binding activity. Predicted to be involved in actin filament polymerization and protein repair. Predicted to be located in mitochondrion. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MSRB2 links:

ENSG00000286924 (HGNC:):

ENSG00000286924 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.065283716).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012228.4. 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
	MSRB2	NM_012228.4	MANE Select	c.74C>T	p.Ala25Val	missense	Exon 1 of 5	NP_036360.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MSRB2	ENST00000376510.8	TSL:1 MANE Select	c.74C>T	p.Ala25Val	missense	Exon 1 of 5	ENSP00000365693.3	Q9Y3D2
MSRB2	ENST00000900184.1		c.74C>T	p.Ala25Val	missense	Exon 1 of 5	ENSP00000570243.1
MSRB2	ENST00000900183.1		c.74C>T	p.Ala25Val	missense	Exon 1 of 5	ENSP00000570242.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1168076

Hom.:

Cov.:

AF XY:

0.00000354

AC XY:

AN XY:

565632

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23220

American (AMR)

AF:

0.00

AC:

AN:

8730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15480

East Asian (EAS)

AF:

0.00

AC:

AN:

26818

South Asian (SAS)

AF:

0.0000235

AC:

AN:

42644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3198

European-Non Finnish (NFE)

AF:

0.00000308

AC:

AN:

974322

Other (OTH)

AF:

0.00

AC:

AN:

47274

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.15

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.50

M_CAP

Benign

0.068

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

PhyloP100

-0.48

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.26

REVEL

Benign

0.028

Sift

Uncertain

0.013

Sift4G

Uncertain

0.034

Polyphen

0.14

Vest4

0.092

MutPred

0.21

Loss of relative solvent accessibility (P = 0.0186)

MVP

0.15

MPC

0.18

ClinPred

0.17

GERP RS

-1.5

PromoterAI

-0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.038

gMVP

0.29

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over