2-215996331-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_018000.3(MREG):c.230G>A(p.Arg77His) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,613,886 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R77C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 1 hom. )

Consequence

MREG
NM_018000.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.54

Variant links:

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 links:

PECR (HGNC:18281): (peroxisomal trans-2-enoyl-CoA reductase) Enables signaling receptor binding activity and trans-2-enoyl-CoA reductase (NADPH) activity. Involved in phytol metabolic process. Located in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

PECR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MREG	NM_018000.3 link	c.230G>A	p.Arg77His	missense_variant	Exon 2 of 5	ENST00000263268.11	NP_060470.2	Q8N565-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MREG	ENST00000263268.11 link	c.230G>A	p.Arg77His	missense_variant	Exon 2 of 5	2	NM_018000.3	ENSP00000263268.6		Q8N565-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000522

AC:

AN:

248986

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461550

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000244

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.230G>A (p.R77H) alteration is located in exon 2 (coding exon 2) of the MREG gene. This alteration results from a G to A substitution at nucleotide position 230, causing the arginine (R) at amino acid position 77 to be replaced by a histidine (H). 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

0.55

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;D;.;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.90

D;.;D;D;D

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.84

D;D;D;D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.3

M;M;.;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.5

.;D;D;D;D

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.90

MutPred

0.80

Loss of catalytic residue at R77 (P = 0.0897);Loss of catalytic residue at R77 (P = 0.0897);.;.;.;

MVP

0.48

MPC

0.48

ClinPred

0.74

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over