NM_002303.6:c.1968G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002303.6(LEPR):c.1968G>C(p.Lys656Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,611,922 control chromosomes in the GnomAD database, including 23,611 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 2494 hom., cov: 33)

Exomes 𝑓: 0.17 ( 21117 hom. )

Consequence

LEPR
NM_002303.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.469

Publications

220 publications found

Variant links:

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

LEPR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019337535).

BP6

Variant 1-65610269-G-C is Benign according to our data. Variant chr1-65610269-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 8524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6 link	c.1968G>C	p.Lys656Asn	missense_variant	Exon 14 of 20	ENST00000349533.11	NP_002294.2	P48357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11 link	c.1968G>C	p.Lys656Asn	missense_variant	Exon 14 of 20	1	NM_002303.6	ENSP00000330393.7		P48357-1

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26619

AN:

151938

Hom.:

2495

Cov.:

show subpopulations

Gnomad AFR

AF:

0.195

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.204

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.0563

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.174

Gnomad OTH

AF:

0.179

GnomAD2 exomes

AF:

0.159

AC:

39679

AN:

250258

AF XY:

0.160

show subpopulations

Gnomad AFR exome

AF:

0.194

Gnomad AMR exome

AF:

0.167

Gnomad ASJ exome

AF:

0.210

Gnomad EAS exome

AF:

0.0522

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.174

Gnomad OTH exome

AF:

0.178

GnomAD4 exome

AF:

0.167

AC:

243993

AN:

1459864

Hom.:

21117

Cov.:

AF XY:

0.167

AC XY:

121425

AN XY:

726234

show subpopulations

African (AFR)

AF:

0.194

AC:

6482

AN:

33418

American (AMR)

AF:

0.170

AC:

7566

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.216

AC:

5636

AN:

26102

East Asian (EAS)

AF:

0.0779

AC:

3088

AN:

39664

South Asian (SAS)

AF:

0.143

AC:

12277

AN:

85984

European-Finnish (FIN)

AF:

0.123

AC:

6555

AN:

53394

Middle Eastern (MID)

AF:

0.246

AC:

1413

AN:

5740

European-Non Finnish (NFE)

AF:

0.172

AC:

190856

AN:

1110622

Other (OTH)

AF:

0.168

AC:

10120

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

9933

19866

29800

39733

49666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6668

13336

20004

26672

33340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.175

AC:

26632

AN:

152058

Hom.:

2494

Cov.:

AF XY:

0.173

AC XY:

12848

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.194

AC:

8060

AN:

41480

American (AMR)

AF:

0.203

AC:

3101

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

765

AN:

3466

East Asian (EAS)

AF:

0.0566

AC:

293

AN:

5180

South Asian (SAS)

AF:

0.127

AC:

609

AN:

4812

European-Finnish (FIN)

AF:

0.126

AC:

1331

AN:

10568

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.174

AC:

11814

AN:

67980

Other (OTH)

AF:

0.176

AC:

371

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1136

2272

3408

4544

5680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

276

552

828

1104

1380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.146

Hom.:

633

Bravo

AF:

0.179

TwinsUK

AF:

0.180

AC:

668

ALSPAC

AF:

0.164

AC:

633

ESP6500AA

AF:

0.188

AC:

828

ESP6500EA

AF:

0.171

AC:

1467

ExAC

AF:

0.158

AC:

19136

Asia WGS

AF:

0.0970

AC:

336

AN:

3478

EpiCase

AF:

0.193

EpiControl

AF:

0.194

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20814201, 22530350, 23315873, 23266707, 18413223, 14970363, 20185531, 12006639, 9175732) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 12, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Obesity due to leptin receptor gene deficiency

Benign:4

Oct 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 19, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

LEPTIN RECEPTOR POLYMORPHISM

Benign:1

Jul 01, 2001

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Monogenic Non-Syndromic Obesity

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.41

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.081

.;.;T;.;.;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.56

T;.;T;T;T;.

MetaRNN

Benign

0.0019

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L;L;L;L

PhyloP100

-0.47

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.12

N;N;N;N;.;N

REVEL

Benign

0.12

Sift

Benign

0.45

T;T;T;T;.;T

Sift4G

Benign

0.10

T;T;T;T;T;T

Polyphen

0.94

P;P;P;.;P;.

Vest4

0.030

MutPred

0.16

Loss of methylation at K656 (P = 0.0183);Loss of methylation at K656 (P = 0.0183);Loss of methylation at K656 (P = 0.0183);Loss of methylation at K656 (P = 0.0183);Loss of methylation at K656 (P = 0.0183);Loss of methylation at K656 (P = 0.0183);

MPC

0.14

ClinPred

0.0037

GERP RS

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.061

gMVP

0.44

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over