Genetic Variant GAREM2:p.Pro680His (chr2-26187671-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001168241.2(GAREM2):c.2039C>A(p.Pro680His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,517,704 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

GAREM2
NM_001168241.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009382814).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001168241.2. 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
	GAREM2	NM_001168241.2	MANE Select	c.2039C>A	p.Pro680His	missense	Exon 6 of 6	NP_001161713.1	Q75VX8-1
	GAREM2	NM_001191033.2		c.1453-44C>A		intron	N/A	NP_001177962.1	Q75VX8-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAREM2	ENST00000401533.7	TSL:1 MANE Select	c.2039C>A	p.Pro680His	missense	Exon 6 of 6	ENSP00000384593.1	Q75VX8-1
GAREM2	ENST00000407684.1	TSL:2	c.1453-44C>A		intron	N/A	ENSP00000384581.1	Q75VX8-3
GAREM2	ENST00000496070.1	TSL:3	n.*213C>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000154

AC:

AN:

123170

AF XY:

0.000108

show subpopulations

Gnomad AFR exome

AF:

0.000932

Gnomad AMR exome

AF:

0.000446

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000212

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000850

AC:

116

AN:

1365422

Hom.:

Cov.:

AF XY:

0.0000730

AC XY:

AN XY:

671066

show subpopulations

African (AFR)

AF:

0.000694

AC:

AN:

30270

American (AMR)

AF:

0.000537

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:

0.0000135

AC:

AN:

74178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48538

Middle Eastern (MID)

AF:

0.000724

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

0.0000565

AC:

AN:

1062266

Other (OTH)

AF:

0.000213

AC:

AN:

56440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000453

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41556

American (AMR)

AF:

0.000523

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.000948

AC:

AN:

2110

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

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.000499

ExAC

AF:

0.000160

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.014

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.37

M_CAP

Benign

0.019

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.0

PhyloP100

2.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

REVEL

Benign

0.066

Sift

Uncertain

0.012

Sift4G

Uncertain

0.011

Polyphen

0.21

Vest4

0.088

MVP

0.21

ClinPred

0.021

GERP RS

3.4

Varity_R

0.065

gMVP

0.20

Mutation Taster

=96/4

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over