2-215947055-C-G

Position:

• chr2-215947055-C-G

Variant summary

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

The NM_018000.3(MREG):​c.314G>C​(p.Arg105Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MREG NM_018000.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

Genes affected

MREG (HGNC:25478): (melanoregulin) Predicted to enable phosphatidylinositol binding activity. Predicted to be involved in melanocyte differentiation; melanosome transport; and phagosome maturation. Predicted to act upstream of or within developmental pigmentation. Predicted to be located in late endosome membrane and melanosome membrane. Predicted to be intrinsic component of organelle membrane. Predicted to be part of protein-containing complex. Predicted to be active in melanosome. [provided by Alliance of Genome Resources, Apr 2022]

MREG (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MREG	NM_018000.3	c.314G>C	p.Arg105Thr	missense_variant	3/5	ENST00000263268.11	NP_060470.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MREG	ENST00000263268.11	c.314G>C	p.Arg105Thr	missense_variant	3/5	2	NM_018000.3	ENSP00000263268.6
MREG	ENST00000439791.5	c.152G>C	p.Arg51Thr	missense_variant	3/5	4		ENSP00000411076.1
MREG	ENST00000424992.5	c.152G>C	p.Arg51Thr	missense_variant	3/5	5		ENSP00000413302.1
MREG	ENST00000420348.1	c.152G>C	p.Arg51Thr	missense_variant	3/4	4		ENSP00000404470.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

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

Jun 30, 2022

The c.314G>C (p.R105T) alteration is located in exon 3 (coding exon 3) of the MREG gene. This alteration results from a G to C substitution at nucleotide position 314, causing the arginine (R) at amino acid position 105 to be replaced by a threonine (T). 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;D;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;.;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.3	M;M;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.2	.;D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0030	.;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;.;.
Polyphen		0.97	D;D;.;.;.
Vest4		0.79
MutPred		0.43		Loss of MoRF binding (P = 0.0336);Loss of MoRF binding (P = 0.0336);.;.;.;
MVP		0.59
MPC		0.53
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.56

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: rs1385499942; hg19: chr2-216811778;