Genetic Variant GAREM2:p.Asp406Ala (chr2-26185065-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.1217A>C(p.Asp406Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000134 in 149,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Consequence

GAREM2
NM_001168241.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.18

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=0.09710574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM2	NM_001168241.2 link	c.1217A>C	p.Asp406Ala	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.1217A>C	p.Asp406Ala	missense_variant	Exon 4 of 6	1	NM_001168241.2	ENSP00000384593.1	Q75VX8-1
GAREM2	ENST00000407684.1 link	c.986A>C	p.Asp329Ala	missense_variant	Exon 3 of 6	2		ENSP00000384581.1	Q75VX8-3
GAREM2	ENST00000496070.1 link	n.-167A>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000490

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149098

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72676

show subpopulations

African (AFR)

AF:

0.0000490

AC:

AN:

40836

American (AMR)

AF:

0.00

AC:

AN:

15012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67062

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1217A>C (p.D406A) 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 1217, causing the aspartic acid (D) at amino acid position 406 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

0.20

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.47

T;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.097

T;T

MetaSVM

Benign

-1.0

PhyloP100

4.2

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.079

Sift

Benign

0.14

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.0050

B;.

Vest4

0.13

MutPred

0.073

Loss of sheet (P = 0.1158);.;

MVP

0.25

ClinPred

0.27

GERP RS

3.4

Varity_R

0.21

gMVP

0.44

Mutation Taster

=80/20

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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2-26185065-A-C

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