rs2186248

Variant names:

• chr1-65570818-G-A
• rs2186248
• NM_002303.6:c.370+16G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-65570818-G-A
• chr1-65570818-G-C
• chr1-65570818-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002303.6(LEPR):​c.370+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.452
• Publications: 6 publications found

Genes affected

LEPR (HGNC:6554): (leptin receptor) The protein encoded by this gene belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight), and is involved in the regulation of fat metabolism, as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Mutations in this gene have been associated with obesity and pituitary dysfunction. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. It is noteworthy that this gene and LEPROT gene (GeneID:54741) share the same promoter and the first 2 exons, however, encode distinct proteins (PMID:9207021).[provided by RefSeq, Nov 2010]

LEPR Gene-Disease associations (from GenCC):

• obesity due to leptin receptor gene deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.370+16G>A		intron_variant	Intron 4 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.370+16G>A		intron_variant	Intron 4 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1373100 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 674334

African (AFR) AF: 0.00 AC: 0 AN: 30488

American (AMR) AF: 0.00 AC: 0 AN: 30554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20908

East Asian (EAS) AF: 0.00 AC: 0 AN: 38888

South Asian (SAS) AF: 0.00 AC: 0 AN: 69356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4922

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071736

Other (OTH) AF: 0.00 AC: 0 AN: 56582

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.78
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2186248; hg19: chr1-66036501;