6-99947914-C-A

Position:

• chr6-99947914-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001040179.2(MCHR2):​c.240G>T​(p.Leu80Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MCHR2 NM_001040179.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.110

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39550903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCHR2	NM_001040179.2	c.240G>T	p.Leu80Phe	missense_variant	3/6	ENST00000281806.7	NP_001035269.1
MCHR2	NM_032503.3	c.240G>T	p.Leu80Phe	missense_variant	3/6		NP_115892.2
MCHR2	XM_024446571.2	c.240G>T	p.Leu80Phe	missense_variant	3/6		XP_024302339.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCHR2	ENST00000281806.7	c.240G>T	p.Leu80Phe	missense_variant	3/6	2	NM_001040179.2	ENSP00000281806.2
MCHR2	ENST00000369212.2	c.240G>T	p.Leu80Phe	missense_variant	3/6	1		ENSP00000358214.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461500 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727052

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

The c.240G>T (p.L80F) alteration is located in exon 3 (coding exon 2) of the MCHR2 gene. This alteration results from a G to T substitution at nucleotide position 240, causing the leucine (L) at amino acid position 80 to be replaced by a phenylalanine (F). 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	0.29
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.047	D;D
Polyphen		0.85	P;P
Vest4		0.43
MutPred		0.57		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.74
MPC		0.41
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.34
gMVP		0.14

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

Other links and lift over

dbSNP: rs78660011; hg19: chr6-100395790; COSMIC: COSV99029585;