rs750630201

Variant names:

• chr2-26183092-G-A
• rs750630201
• NM_001168241.2:c.379G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-26183092-G-A
• chr2-26183092-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001168241.2(GAREM2):​c.379G>A​(p.Val127Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,551,644 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 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GAREM2 NM_001168241.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66
• Publications: 6 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07788339).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAREM2	NM_001168241.2	c.379G>A	p.Val127Ile	missense_variant	Exon 3 of 6	ENST00000401533.7	NP_001161713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAREM2	ENST00000401533.7	c.379G>A	p.Val127Ile	missense_variant	Exon 3 of 6	1	NM_001168241.2	ENSP00000384593.1
GAREM2	ENST00000407684.1	c.148G>A	p.Val50Ile	missense_variant	Exon 2 of 6	2		ENSP00000384581.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000787 AC: 12 AN: 152440 AF XY: 0.0000864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000459

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000250 AC: 35 AN: 1399346 Hom.: 0 Cov.: 31 AF XY: 0.0000290 AC XY: 20 AN XY: 690194

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.000168 AC: 6 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.000196 AC: 7 AN: 35734

South Asian (SAS) AF: 0.000101 AC: 8 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49292

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5680

European-Non Finnish (NFE) AF: 0.00000463 AC: 5 AN: 1078922

Other (OTH) AF: 0.000138 AC: 8 AN: 58008

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000387 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.379G>A (p.V127I) alteration is located in exon 3 (coding exon 3) of the GAREM2 gene. This alteration results from a G to A substitution at nucleotide position 379, causing the valine (V) at amino acid position 127 to be replaced by an isoleucine (I). 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	0.27
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.030	T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		7.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.76	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.99	D;.
Vest4		0.34
MutPred		0.37		Loss of catalytic residue at V127 (P = 0.0319);.;
MVP		0.30
ClinPred		0.22	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.47
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs750630201; hg19: chr2-26405961; COSMIC: COSV68225749; COSMIC: COSV68225749;