12-108292134-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001142343.2(CMKLR1):c.829C>G(p.His277Asp) 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CMKLR1	NM_001142343.2	c.829C>G	p.His277Asp	missense_variant	4/4	ENST00000550402.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CMKLR1	ENST00000550402.6	c.829C>G	p.His277Asp	missense_variant	4/4	1	NM_001142343.2	A1
CMKLR1	ENST00000552995.5	c.823C>G	p.His275Asp	missense_variant	3/3	1		P4
CMKLR1	ENST00000312143.11	c.829C>G	p.His277Asp	missense_variant	3/3	2		A1
CMKLR1	ENST00000412676.5	c.829C>G	p.His277Asp	missense_variant	3/3	3		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

Dec 01, 2022

The c.829C>G (p.H277D) alteration is located in exon 4 (coding exon 2) of the CMKLR1 gene. This alteration results from a C to G substitution at nucleotide position 829, causing the histidine (H) at amino acid position 277 to be replaced by an aspartic acid (D). 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	0.95
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T;.;T;.
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.048	D
MutationAssessor	Pathogenic	4.6	H;H;.;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-8.5	D;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.78
MutPred		0.75		Gain of catalytic residue at W273 (P = 0);Gain of catalytic residue at W273 (P = 0);.;Gain of catalytic residue at W273 (P = 0);
MVP		0.87
MPC		0.77
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.88

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: chr12-108685911;