2-215996352-A-T

Variant names:

• chr2-215996352-A-T
• rs373470737
• NM_018000.3:c.209T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018000.3(MREG):​c.209T>A​(p.Leu70Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L70P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MREG NM_018000.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.37
• Publications: 0 publications found

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]

PECR Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018000.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MREG	NM_018000.3	MANE Select	c.209T>A	p.Leu70Gln	missense	Exon 2 of 5	NP_060470.2	Q8N565-1
	MREG	NM_001372188.1		c.209T>A	p.Leu70Gln	missense	Exon 2 of 6	NP_001359117.1
	MREG	NM_001372189.1		c.47T>A	p.Leu16Gln	missense	Exon 2 of 5	NP_001359118.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MREG	ENST00000263268.11	TSL:2 MANE Select	c.209T>A	p.Leu70Gln	missense	Exon 2 of 5	ENSP00000263268.6	Q8N565-1
	MREG	ENST00000439791.5	TSL:4	c.47T>A	p.Leu16Gln	missense	Exon 2 of 5	ENSP00000411076.1	C9JAG4
	MREG	ENST00000424992.5	TSL:5	c.47T>A	p.Leu16Gln	missense	Exon 2 of 5	ENSP00000413302.1	C9JYV9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461662 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111852

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.56		Gain of disorder (P = 0.0413)
MVP		0.52
MPC		0.45
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.79
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs373470737; hg19: chr2-216861075;