2-215996331-C-T

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

6
11
2

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]
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]

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
MREGNM_018000.3 linkc.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
MREGENST00000263268.11 linkc.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:
1
AN:
152218
Hom.:
0
Cov.:
33
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:
13
AN:
248986
Hom.:
1
AF XY:
0.0000518
AC XY:
7
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:
27
AN:
1461550
Hom.:
1
Cov.:
31
AF XY:
0.0000289
AC XY:
21
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:
1
AN:
152336
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
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:
4

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
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.60
D;D;.;.;.
Eigen
Uncertain
0.68
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.90
D;.;D;D;D
M_CAP
Benign
0.049
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Uncertain
2.3
M;M;.;.;.
PrimateAI
Uncertain
0.57
T
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
D
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.

Other links and lift over

dbSNP: rs572090838; hg19: chr2-216861054; API