2-26187532-T-C

Position:

• chr2-26187532-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001168241.2(GAREM2):​c.1900T>C​(p.Ser634Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: GAREM2 NM_001168241.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15065077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAREM2	NM_001168241.2	c.1900T>C	p.Ser634Pro	missense_variant	6/6	ENST00000401533.7	NP_001161713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAREM2	ENST00000401533.7	c.1900T>C	p.Ser634Pro	missense_variant	6/6	1	NM_001168241.2	ENSP00000384593	P1
GAREM2	ENST00000407684.1	c.1453-183T>C		intron_variant		2		ENSP00000384581

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000728 AC: 1 AN: 137454 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 72956

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000362 AC: 1

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

Sep 17, 2021

The c.1900T>C (p.S634P) alteration is located in exon 6 (coding exon 6) of the GAREM2 gene. This alteration results from a T to C substitution at nucleotide position 1900, causing the serine (S) at amino acid position 634 to be replaced by a proline (P). 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	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		0.93	P
Vest4		0.22
MutPred		0.12		Loss of glycosylation at S634 (P = 0.0287);
MVP		0.11
ClinPred		0.15	T
GERP RS		2.8
Varity_R		0.20
gMVP		0.35

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: rs755174597; hg19: chr2-26410401;