Genetic Variant GAREM2:p.Gly440Asp (chr2-26185167-G-A) – 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.1319G>A(p.Gly440Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000443 in 1,354,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000044 ( 0 hom. )

Consequence

GAREM2
NM_001168241.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

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: 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=0.04888645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM2	NM_001168241.2 link	c.1319G>A	p.Gly440Asp	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.1319G>A	p.Gly440Asp	missense_variant	Exon 4 of 6	1	NM_001168241.2	ENSP00000384593.1	Q75VX8-1
GAREM2	ENST00000407684.1 link	c.1088G>A	p.Gly363Asp	missense_variant	Exon 3 of 6	2		ENSP00000384581.1	Q75VX8-3
GAREM2	ENST00000496070.1 link	n.-65G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000443

AC:

AN:

1354964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

668226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27876

American (AMR)

AF:

0.00

AC:

AN:

33214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24056

East Asian (EAS)

AF:

0.00

AC:

AN:

31776

South Asian (SAS)

AF:

0.00

AC:

AN:

77142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4002

European-Non Finnish (NFE)

AF:

0.00000562

AC:

AN:

1067256

Other (OTH)

AF:

0.00

AC:

AN:

56480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1319G>A (p.G440D) alteration is located in exon 4 (coding exon 4) of the GAREM2 gene. This alteration results from a G to A substitution at nucleotide position 1319, causing the glycine (G) at amino acid position 440 to be replaced by an aspartic acid (D). 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

0.97

DEOGEN2

Benign

0.0079

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.48

T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-0.98

PhyloP100

1.1

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.47

N;N

REVEL

Benign

0.014

Sift

Benign

0.39

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.0010

B;.

Vest4

0.041

MutPred

0.30

Gain of solvent accessibility (P = 0.039);.;

MVP

0.11

ClinPred

0.090

GERP RS

2.8

Varity_R

0.080

gMVP

0.34

Mutation Taster

=93/7

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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2-26185167-G-A

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