chr2-48688732-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000233.4(LHCGR):c.1065T>C(p.Asp355Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 1,613,476 control chromosomes in the GnomAD database, including 282,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 22710 hom., cov: 31)

Exomes 𝑓: 0.59 ( 259603 hom. )

Consequence

LHCGR
NM_000233.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.456

Publications

21 publications found

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 was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 2-48688732-A-G is Benign according to our data. Variant chr2-48688732-A-G is described in ClinVar as Benign. ClinVar VariationId is 255607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.456 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHCGR	NM_000233.4 link	c.1065T>C	p.Asp355Asp	synonymous_variant	Exon 11 of 11	ENST00000294954.12	NP_000224.2	P22888-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12 link	c.1065T>C	p.Asp355Asp	synonymous_variant	Exon 11 of 11	1	NM_000233.4	ENSP00000294954.6		P22888-1
ENSG00000279956	ENST00000602369.3 link	n.*220+5492T>C		intron_variant	Intron 9 of 12	5		ENSP00000473498.1		R4GN57

Frequencies

GnomAD3 genomes

AF:

0.527

AC:

80031

AN:

151860

Hom.:

22709

Cov.:

show subpopulations

Gnomad AFR

AF:

0.313

Gnomad AMI

AF:

0.493

Gnomad AMR

AF:

0.634

Gnomad ASJ

AF:

0.644

Gnomad EAS

AF:

0.929

Gnomad SAS

AF:

0.605

Gnomad FIN

AF:

0.579

Gnomad MID

AF:

0.657

Gnomad NFE

AF:

0.581

Gnomad OTH

AF:

0.569

GnomAD2 exomes

AF:

0.614

AC:

154217

AN:

251310

AF XY:

0.612

show subpopulations

Gnomad AFR exome

AF:

0.303

Gnomad AMR exome

AF:

0.708

Gnomad ASJ exome

AF:

0.669

Gnomad EAS exome

AF:

0.930

Gnomad FIN exome

AF:

0.574

Gnomad NFE exome

AF:

0.584

Gnomad OTH exome

AF:

0.616

GnomAD4 exome

AF:

0.591

AC:

863015

AN:

1461496

Hom.:

259603

Cov.:

AF XY:

0.591

AC XY:

429728

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.306

AC:

10238

AN:

33476

American (AMR)

AF:

0.698

AC:

31226

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.664

AC:

17357

AN:

26134

East Asian (EAS)

AF:

0.936

AC:

37144

AN:

39700

South Asian (SAS)

AF:

0.600

AC:

51711

AN:

86252

European-Finnish (FIN)

AF:

0.573

AC:

30627

AN:

53418

Middle Eastern (MID)

AF:

0.695

AC:

4010

AN:

5766

European-Non Finnish (NFE)

AF:

0.580

AC:

644231

AN:

1111640

Other (OTH)

AF:

0.604

AC:

36471

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

19368

38736

58104

77472

96840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17834

35668

53502

71336

89170

<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:

0.527

AC:

80067

AN:

151980

Hom.:

22710

Cov.:

AF XY:

0.534

AC XY:

39678

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.313

AC:

12970

AN:

41438

American (AMR)

AF:

0.634

AC:

9678

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.644

AC:

2235

AN:

3472

East Asian (EAS)

AF:

0.929

AC:

4797

AN:

5164

South Asian (SAS)

AF:

0.606

AC:

2921

AN:

4818

European-Finnish (FIN)

AF:

0.579

AC:

6118

AN:

10566

Middle Eastern (MID)

AF:

0.648

AC:

188

AN:

290

European-Non Finnish (NFE)

AF:

0.581

AC:

39513

AN:

67956

Other (OTH)

AF:

0.569

AC:

1198

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1791

3583

5374

7166

8957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<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:

0.572

Hom.:

49585

Bravo

AF:

0.526

Asia WGS

AF:

0.700

AC:

2437

AN:

3478

EpiCase

AF:

0.590

EpiControl

AF:

0.594

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 26, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Jan 12, 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. -

Gonadotropin-independent familial sexual precocity

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

3.3

(source)

DANN

Benign

0.74

PhyloP100

0.46

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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