6-99921148-A-G

Position:

• chr6-99921148-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001040179.2(MCHR2):​c.815T>C​(p.Leu272Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCHR2 NM_001040179.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCHR2	NM_001040179.2	c.815T>C	p.Leu272Pro	missense_variant	6/6	ENST00000281806.7	NP_001035269.1
MCHR2	NM_032503.3	c.815T>C	p.Leu272Pro	missense_variant	6/6		NP_115892.2
MCHR2	XM_024446571.2	c.815T>C	p.Leu272Pro	missense_variant	6/6		XP_024302339.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCHR2	ENST00000281806.7	c.815T>C	p.Leu272Pro	missense_variant	6/6	2	NM_001040179.2	ENSP00000281806	P1
MCHR2	ENST00000369212.2	c.815T>C	p.Leu272Pro	missense_variant	6/6	1		ENSP00000358214	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

May 27, 2022

The c.815T>C (p.L272P) alteration is located in exon 6 (coding exon 5) of the MCHR2 gene. This alteration results from a T to C substitution at nucleotide position 815, causing the leucine (L) at amino acid position 272 to be replaced by a proline (P). 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T;.
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.5	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.84		Loss of stability (P = 0.0371);Loss of stability (P = 0.0371);
MVP		0.98
MPC		0.48
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-100369024;