2-215996448-G-A

Position:

• chr2-215996448-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_018000.3(MREG):​c.113C>T​(p.Ser38Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,612,122 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (5 hom.)
• Consequence: MREG NM_018000.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.99

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019039124).
• BP6: Variant 2-215996448-G-A is Benign according to our data. Variant chr2-215996448-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3351809.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MREG	NM_018000.3	c.113C>T	p.Ser38Phe	missense_variant	2/5	ENST00000263268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MREG	ENST00000263268.11	c.113C>T	p.Ser38Phe	missense_variant	2/5	2	NM_018000.3	P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00122 AC: 301 AN: 247562 Hom.: 0 AF XY: 0.00127 AC XY: 171 AN XY: 134256

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000616

Gnomad ASJ exome AF: 0.00420

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000730

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00180 AC: 2625 AN: 1459832 Hom.: 5 Cov.: 30 AF XY: 0.00175 AC XY: 1268 AN XY: 726184

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000767

Gnomad4 ASJ exome AF: 0.00433

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000722

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00202

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74470

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00172 Hom.: 1

Bravo AF: 0.00154

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000271 AC: 1

ESP6500EA AF: 0.00232 AC: 19

ExAC AF: 0.00116 AC: 140

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00191

EpiControl AF: 0.00136

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MREG-related condition Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.85	D;.
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.98	L;L
MutationTaster	Benign	0.63	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.51	.;N
REVEL	Benign	0.10
Sift	Benign	0.20	.;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;D
Vest4		0.50
MVP		0.39
MPC		0.31
ClinPred		0.027	T
GERP RS		5.3
Varity_R		0.051
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200466592; hg19: chr2-216861171;