Genetic Variant GAREM2:p.Glu404Ala (chr2-26185059-A-C) – 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.1211A>C(p.Glu404Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GAREM2
NM_001168241.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

Publications

0 publications found

Variant links:

Genes affected

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

GAREM2 links:

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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=0.10862619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM2	NM_001168241.2 link	c.1211A>C	p.Glu404Ala	missense_variant	Exon 4 of 6	ENST00000401533.7	NP_001161713.1	Q75VX8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GAREM2	ENST00000401533.7 link	c.1211A>C	p.Glu404Ala	missense_variant	Exon 4 of 6	1	NM_001168241.2	ENSP00000384593.1	Q75VX8-1
GAREM2	ENST00000407684.1 link	c.980A>C	p.Glu327Ala	missense_variant	Exon 3 of 6	2		ENSP00000384581.1	Q75VX8-3
GAREM2	ENST00000496070.1 link	n.-173A>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1095996

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

522852

African (AFR)

AF:

0.00

AC:

AN:

22510

American (AMR)

AF:

0.00

AC:

AN:

8086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14400

East Asian (EAS)

AF:

0.00

AC:

AN:

25712

South Asian (SAS)

AF:

0.00

AC:

AN:

27986

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2920

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

928072

Other (OTH)

AF:

0.00

AC:

AN:

43684

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

Aug 16, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1211A>C (p.E404A) alteration is located in exon 4 (coding exon 4) of the GAREM2 gene. This alteration results from a A to C substitution at nucleotide position 1211, causing the glutamic acid (E) at amino acid position 404 to be replaced by an alanine (A). 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

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.016

T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.47

T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.0

PhyloP100

4.2

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.037

Sift

Uncertain

0.010

D;D

Sift4G

Benign

0.56

T;T

Polyphen

0.0070

B;.

Vest4

0.097

MutPred

0.13

Loss of solvent accessibility (P = 0.0769);.;

MVP

0.095

ClinPred

0.37

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.18

gMVP

0.48

Mutation Taster

=79/21

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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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