6-99934458-C-A

Variant names:

• chr6-99934458-C-A
• NM_001040179.2:c.647G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001040179.2(MCHR2):​c.647G>T​(p.Cys216Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,454 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MCHR2 NM_001040179.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.925

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCHR2	NM_001040179.2	c.647G>T	p.Cys216Phe	missense_variant	Exon 5 of 6	ENST00000281806.7	NP_001035269.1
MCHR2	NM_032503.3	c.647G>T	p.Cys216Phe	missense_variant	Exon 5 of 6		NP_115892.2
MCHR2	XM_024446571.2	c.647G>T	p.Cys216Phe	missense_variant	Exon 5 of 6		XP_024302339.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCHR2	ENST00000281806.7	c.647G>T	p.Cys216Phe	missense_variant	Exon 5 of 6	2	NM_001040179.2	ENSP00000281806.2
MCHR2	ENST00000369212.2	c.647G>T	p.Cys216Phe	missense_variant	Exon 5 of 6	1		ENSP00000358214.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452454 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.647G>T (p.C216F) alteration is located in exon 5 (coding exon 4) of the MCHR2 gene. This alteration results from a G to T substitution at nucleotide position 647, causing the cysteine (C) at amino acid position 216 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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.57	T;.
M_CAP	Benign	0.0083	T
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.33
Sift	Benign	0.27	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.97	D;D
Vest4		0.49
MutPred		0.67		Loss of catalytic residue at C216 (P = 0.1828);Loss of catalytic residue at C216 (P = 0.1828);
MVP		0.86
MPC		0.40
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.77
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-100382334;