Genetic Variant GAREM2:p.Pro680Leu (chr2-26187671-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_001168241.2(GAREM2):c.2039C>T(p.Pro680Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000527 in 1,517,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. P680H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

GAREM2
NM_001168241.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.45

Publications

1 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: 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=0.06336975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM2	NM_001168241.2 link	c.2039C>T	p.Pro680Leu	missense_variant	Exon 6 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.2039C>T	p.Pro680Leu	missense_variant	Exon 6 of 6	1	NM_001168241.2	ENSP00000384593.1	Q75VX8-1
GAREM2	ENST00000407684.1 link	c.1453-44C>T		intron_variant	Intron 5 of 5	2		ENSP00000384581.1	Q75VX8-3
GAREM2	ENST00000496070.1 link	n.*213C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000812

AC:

AN:

123170

AF XY:

0.0000154

show subpopulations

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:

0.00000439

AC:

AN:

1365422

Hom.:

Cov.:

AF XY:

0.00000447

AC XY:

AN XY:

671066

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30270

American (AMR)

AF:

0.00

AC:

AN:

29810

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23046

East Asian (EAS)

AF:

0.0000566

AC:

AN:

35352

South Asian (SAS)

AF:

0.0000404

AC:

AN:

74178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

9.41e-7

AC:

AN:

1062266

Other (OTH)

AF:

0.00

AC:

AN:

56440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0078

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.55

M_CAP

Benign

0.013

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.1

PhyloP100

2.5

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.98

REVEL

Benign

0.062

Sift

Benign

0.069

Sift4G

Uncertain

0.027

Polyphen

0.0080

Vest4

0.064

MutPred

0.20

Loss of relative solvent accessibility (P = 0.0071);

MVP

0.42

ClinPred

0.065

GERP RS

3.4

Varity_R

0.028

gMVP

0.19

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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2-26187671-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over