2-26185065-A-C

Position:

• chr2-26185065-A-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.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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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=0.09710574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAREM2	NM_001168241.2	c.1217A>C	p.Asp406Ala	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.1217A>C	p.Asp406Ala	missense_variant	4/6	1	NM_001168241.2	ENSP00000384593	P1
GAREM2	ENST00000407684.1	c.986A>C	p.Asp329Ala	missense_variant	3/6	2		ENSP00000384581

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149098 Hom.: 0 Cov.: 33

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.: 28

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149098 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 1 AN XY: 72676

Gnomad4 AFR AF: 0.0000490

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

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 10, 2021

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	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.88
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.47	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Pathogenic	0.92	D
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	T
GERP RS		3.4
Varity_R		0.21
gMVP		0.44

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: rs1327531303; hg19: chr2-26407934;