12-108292139-G-A

Position:

• chr12-108292139-G-A

Variant summary

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

The NM_001142343.2(CMKLR1):​c.824C>T​(p.Pro275Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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: CMKLR1 NM_001142343.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99

Genes affected

CMKLR1 (HGNC:2121): (chemerin chemokine-like receptor 1) Enables adipokinetic hormone binding activity and adipokinetic hormone receptor activity. Involved in several processes, including negative regulation of NF-kappaB transcription factor activity; positive regulation of macrophage chemotaxis; and regulation of calcium-mediated signaling. Located in 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, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CMKLR1	NM_001142343.2	c.824C>T	p.Pro275Leu	missense_variant	4/4	ENST00000550402.6	NP_001135815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CMKLR1	ENST00000550402.6	c.824C>T	p.Pro275Leu	missense_variant	4/4	1	NM_001142343.2	ENSP00000449716	A1
CMKLR1	ENST00000552995.5	c.818C>T	p.Pro273Leu	missense_variant	3/3	1		ENSP00000447579	P4
CMKLR1	ENST00000312143.11	c.824C>T	p.Pro275Leu	missense_variant	3/3	2		ENSP00000311733	A1
CMKLR1	ENST00000412676.5	c.824C>T	p.Pro275Leu	missense_variant	3/3	3		ENSP00000401293	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jul 25, 2023

The c.824C>T (p.P275L) alteration is located in exon 4 (coding exon 2) of the CMKLR1 gene. This alteration results from a C to T substitution at nucleotide position 824, causing the proline (P) at amino acid position 275 to be replaced by a leucine (L). 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	0.82
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;.;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.9	H;H;.;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-9.8	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.93
MutPred		0.77		Gain of catalytic residue at L271 (P = 0);Gain of catalytic residue at L271 (P = 0);.;Gain of catalytic residue at L271 (P = 0);
MVP		0.98
MPC		0.66
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.85

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: chr12-108685916;