rs544952908

Variant names:

• chr2-26187671-C-A
• rs544952908
• NM_001168241.2:c.2039C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-26187671-C-A
• chr2-26187671-C-G
• chr2-26187671-C-T

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45
• Publications: 1 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009382814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM2	NM_001168241.2	c.2039C>A	p.Pro680His	missense_variant	Exon 6 of 6	ENST00000401533.7	NP_001161713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAREM2	ENST00000401533.7	c.2039C>A	p.Pro680His	missense_variant	Exon 6 of 6	1	NM_001168241.2	ENSP00000384593.1
GAREM2	ENST00000407684.1	c.1453-44C>A		intron_variant	Intron 5 of 5	2		ENSP00000384581.1
GAREM2	ENST00000496070.1	n.*213C>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152164 Hom.: 0 Cov.: 33

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: 19 AN: 123170 AF XY: 0.000108

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.: 0 Cov.: 32 AF XY: 0.0000730 AC XY: 49 AN XY: 671066

African (AFR) AF: 0.000694 AC: 21 AN: 30270

American (AMR) AF: 0.000537 AC: 16 AN: 29810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23046

East Asian (EAS) AF: 0.0000566 AC: 2 AN: 35352

South Asian (SAS) AF: 0.0000135 AC: 1 AN: 74178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48538

Middle Eastern (MID) AF: 0.000724 AC: 4 AN: 5522

European-Non Finnish (NFE) AF: 0.0000565 AC: 60 AN: 1062266

Other (OTH) AF: 0.000213 AC: 12 AN: 56440

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74466

African (AFR) AF: 0.00137 AC: 57 AN: 41556

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000499

ExAC AF: 0.000160 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2039C>A (p.P680H) alteration is located in exon 6 (coding exon 6) of the GAREM2 gene. This alteration results from a C to A substitution at nucleotide position 2039, causing the proline (P) at amino acid position 680 to be replaced by a histidine (H). 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	0.094
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.066
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.011	D
Polyphen		0.21	B
Vest4		0.088
MVP		0.21
ClinPred		0.021	T
GERP RS		3.4
Varity_R		0.065
gMVP		0.20
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs544952908; hg19: chr2-26410540;