rs2293275

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000233.4(LHCGR):c.935A>G(p.Asn312Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,565,618 control chromosomes in the GnomAD database, including 273,076 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 22631 hom., cov: 33)

Exomes 𝑓: 0.59 ( 250445 hom. )

Consequence

LHCGR
NM_000233.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.19

Variant links:

Genes affected

LHCGR (HGNC:6585): (luteinizing hormone/choriogonadotropin receptor) This gene encodes the receptor for both luteinizing hormone and choriogonadotropin. This receptor belongs to the G-protein coupled receptor 1 family, and its activity is mediated by G proteins which activate adenylate cyclase. Mutations in this gene result in disorders of male secondary sexual character development, including familial male precocious puberty, also known as testotoxicosis, hypogonadotropic hypogonadism, Leydig cell adenoma with precocious puberty, and male pseudohermaphtoditism with Leydig cell hypoplasia. [provided by RefSeq, Jul 2008]

LHCGR links:

ENSG00000279956 (HGNC:):

ENSG00000279956 links:

STON1-GTF2A1L (HGNC:30651): (STON1-GTF2A1L readthrough) STON1-GTF2A1L mRNAs are infrequent but naturally occurring read-through products of the neighboring STON1 and GTF2A1L genes. These transcripts encode fusion proteins composed of the vast majority of each of the individual elements, stonin 1 and general transcription factor IIA, 1-like. Alternative splicing results in multiple transcript variants. The significance of these read-through variants and the function of the resulting protein products have not yet been determined. [provided by RefSeq, Oct 2010]

STON1-GTF2A1L links:

GTF2A1L (HGNC:30727): (general transcription factor IIA subunit 1 like) The assembly and stability of the RNA polymerase II transcription pre-initiation complex on a eukaryotic core promoter involve the effects of transcription factor IIA (TFIIA) on the interaction between TATA-binding protein (TBP) and DNA. This gene encodes a germ cell-specific counterpart of the large (alpha/beta) subunit of general transcription factor TFIIA that is able to stabilize the binding of TBP to DNA and may be uniquely important to testis biology. Alternative splicing for this locus has been observed and two variants, encoding distinct isoforms, have been identified. Co-transcription of this gene and the neighboring upstream gene generates a rare transcript (SALF), which encodes a fusion protein comprised of sequence sharing identity with each individual gene product. [provided by RefSeq, Mar 2014]

GTF2A1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 2-48694236-T-C is Benign according to our data. Variant chr2-48694236-T-C is described in ClinVar as [Benign]. Clinvar id is 255609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48694236-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHCGR	NM_000233.4 link	c.935A>G	p.Asn312Ser	missense_variant	Exon 10 of 11	ENST00000294954.12	NP_000224.2	P22888-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LHCGR	ENST00000294954.12 link	c.935A>G	p.Asn312Ser	missense_variant	Exon 10 of 11	1	NM_000233.4	ENSP00000294954.6	P22888-1
ENSG00000279956	ENST00000602369.3 link	n.*208A>G		non_coding_transcript_exon_variant	Exon 9 of 13	5		ENSP00000473498.1	R4GN57
ENSG00000279956	ENST00000602369.3 link	n.*208A>G		3_prime_UTR_variant	Exon 9 of 13	5		ENSP00000473498.1	R4GN57

Frequencies

GnomAD3 genomes

AF:

0.524

AC:

79577

AN:

151958

Hom.:

22629

Cov.:

show subpopulations

Gnomad AFR

AF:

0.298

Gnomad AMI

AF:

0.491

Gnomad AMR

AF:

0.635

Gnomad ASJ

AF:

0.644

Gnomad EAS

AF:

0.932

Gnomad SAS

AF:

0.619

Gnomad FIN

AF:

0.580

Gnomad MID

AF:

0.649

Gnomad NFE

AF:

0.581

Gnomad OTH

AF:

0.568

GnomAD3 exomes

AF:

0.613

AC:

143913

AN:

234642

Hom.:

46054

AF XY:

0.613

AC XY:

77420

AN XY:

126368

show subpopulations

Gnomad AFR exome

AF:

0.287

Gnomad AMR exome

AF:

0.707

Gnomad ASJ exome

AF:

0.670

Gnomad EAS exome

AF:

0.930

Gnomad SAS exome

AF:

0.612

Gnomad FIN exome

AF:

0.572

Gnomad NFE exome

AF:

0.582

Gnomad OTH exome

AF:

0.621

GnomAD4 exome

AF:

0.589

AC:

832319

AN:

1413542

Hom.:

250445

Cov.:

AF XY:

0.590

AC XY:

415494

AN XY:

704166

show subpopulations

Gnomad4 AFR exome

AF:

0.291

Gnomad4 AMR exome

AF:

0.697

Gnomad4 ASJ exome

AF:

0.663

Gnomad4 EAS exome

AF:

0.937

Gnomad4 SAS exome

AF:

0.612

Gnomad4 FIN exome

AF:

0.573

Gnomad4 NFE exome

AF:

0.577

Gnomad4 OTH exome

AF:

0.603

GnomAD4 genome

AF:

0.523

AC:

79610

AN:

152076

Hom.:

22631

Cov.:

AF XY:

0.531

AC XY:

39499

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.298

Gnomad4 AMR

AF:

0.635

Gnomad4 ASJ

AF:

0.644

Gnomad4 EAS

AF:

0.932

Gnomad4 SAS

AF:

0.620

Gnomad4 FIN

AF:

0.580

Gnomad4 NFE

AF:

0.581

Gnomad4 OTH

AF:

0.568

Alfa

AF:

0.586

Hom.:

66336

Bravo

AF:

0.522

TwinsUK

AF:

0.575

AC:

2131

ALSPAC

AF:

0.590

AC:

2272

ESP6500AA

AF:

0.297

AC:

1307

ESP6500EA

AF:

0.591

AC:

5074

ExAC

AF:

0.592

AC:

71626

Asia WGS

AF:

0.707

AC:

2459

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

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 provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26662070, 22882535, 24792890, 22356187) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypergonadotropic hypogonadism

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leydig cell agenesis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gonadotropin-independent familial sexual precocity

Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.078

T;.;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.62

T;T;T

MetaRNN

Benign

9.4e-7

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.73

N;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

0.080

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.72

T;T;T

Sift4G

Benign

0.77

T;T;T

Polyphen

0.0040

B;.;.

Vest4

0.067

MPC

0.068

ClinPred

0.0051

GERP RS

3.9

Varity_R

0.043

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.35

Position offset: -12

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over