Genetic Variant NM_001168241.2:c.560T>G (chr2-26184408-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001168241.2(GAREM2):c.560T>G(p.Val187Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000749 in 1,335,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

GAREM2
NM_001168241.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.823

Publications

0 publications found

Variant links:

Genes affected

GAREM2 (HGNC:27172): (GRB2 associated regulator of MAPK1 subtype 2)

GAREM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1681292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM2	NM_001168241.2 link	c.560T>G	p.Val187Gly	missense_variant	Exon 4 of 6	ENST00000401533.7	NP_001161713.1	Q75VX8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAREM2	ENST00000401533.7 link	c.560T>G	p.Val187Gly	missense_variant	Exon 4 of 6	1	NM_001168241.2	ENSP00000384593.1		Q75VX8-1
GAREM2	ENST00000407684.1 link	c.329T>G	p.Val110Gly	missense_variant	Exon 3 of 6	2		ENSP00000384581.1		Q75VX8-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.49e-7

AC:

AN:

1335800

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

658722

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:

26864

American (AMR)

AF:

0.00

AC:

AN:

27750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23024

East Asian (EAS)

AF:

0.00

AC:

AN:

28924

South Asian (SAS)

AF:

0.00

AC:

AN:

74068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46700

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5224

European-Non Finnish (NFE)

AF:

9.54e-7

AC:

AN:

1048664

Other (OTH)

AF:

0.00

AC:

AN:

54582

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Sep 17, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.560T>G (p.V187G) alteration is located in exon 4 (coding exon 4) of the GAREM2 gene. This alteration results from a T to G substitution at nucleotide position 560, causing the valine (V) at amino acid position 187 to be replaced by a glycine (G). 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

0.078

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.011

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.27

T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.98

PhyloP100

0.82

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.087

Sift

Benign

0.033

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.0

B;.

Vest4

0.28

MutPred

0.29

Gain of relative solvent accessibility (P = 0.0023);.;

MVP

0.43

ClinPred

0.13

GERP RS

3.9

Varity_R

0.19

gMVP

0.42

Mutation Taster

=97/3

polymorphism

(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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NM_001168241.2:c.560T>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over