Genetic Variant MCHR2:p.Arg140Gln (chr6-99943117-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001040179.2(MCHR2):c.419G>A(p.Arg140Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,609,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. R140L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MCHR2
NM_001040179.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.129

Variant links:

Genes affected

MCHR2 (HGNC:20867): (melanin concentrating hormone receptor 2) Predicted to enable G protein-coupled peptide receptor activity. Predicted to be involved in neuropeptide signaling pathway. Predicted to be located in plasma membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

MCHR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23766544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCHR2	NM_001040179.2 link	c.419G>A	p.Arg140Gln	missense_variant	Exon 4 of 6	ENST00000281806.7	NP_001035269.1	Q969V1
MCHR2	NM_032503.3 link	c.419G>A	p.Arg140Gln	missense_variant	Exon 4 of 6		NP_115892.2	Q969V1
MCHR2	XM_024446571.2 link	c.419G>A	p.Arg140Gln	missense_variant	Exon 4 of 6		XP_024302339.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCHR2	ENST00000281806.7 link	c.419G>A	p.Arg140Gln	missense_variant	Exon 4 of 6	2	NM_001040179.2	ENSP00000281806.2		Q969V1
MCHR2	ENST00000369212.2 link	c.419G>A	p.Arg140Gln	missense_variant	Exon 4 of 6	1		ENSP00000358214.1		Q969V1

Frequencies

GnomAD3 genomes

AF:

0.0000988

AC:

AN:

151828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

250120

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135182

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000125

AC:

182

AN:

1457776

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

725152

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000146

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.0000988

AC:

AN:

151828

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74136

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000177

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.419G>A (p.R140Q) alteration is located in exon 4 (coding exon 3) of the MCHR2 gene. This alteration results from a G to A substitution at nucleotide position 419, causing the arginine (R) at amino acid position 140 to be replaced by a glutamine (Q). 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

Benign

0.095

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.73

T;.

M_CAP

Benign

0.0068

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.052

Sift

Benign

0.072

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.58

P;P

Vest4

0.30

MVP

0.66

MPC

0.087

ClinPred

0.081

GERP RS

1.2

Varity_R

0.12

gMVP

0.24

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