2-26185167-G-A

Position:

• chr2-26185167-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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. 13/19 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -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/exons	MANE	Protein	UniProt
GAREM2	NM_001168241.2	c.1319G>A	p.Gly440Asp	missense_variant	4/6	ENST00000401533.7	NP_001161713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAREM2	ENST00000401533.7	c.1319G>A	p.Gly440Asp	missense_variant	4/6	1	NM_001168241.2	ENSP00000384593	P1
GAREM2	ENST00000407684.1	c.1088G>A	p.Gly363Asp	missense_variant	3/6	2		ENSP00000384581

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000443 AC: 6 AN: 1354964 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 668226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000562

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

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	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.0079	T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.95	N;N
PrimateAI	Pathogenic	0.87	D
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	T
GERP RS		2.8
Varity_R		0.080
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs1669202165; hg19: chr2-26408036;