2-48755616-GGCTGCA-GGCTGCAGCTGCAGCAGCAGCAGCAGCTTCAGCAGCTGCA

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP5_ModerateBP3

The NM_000233.4(LHCGR):c.55_56insTGCTGAAGCTGCTGCTGCTGCTGCAGCTGCAGC(p.Gln18_Pro19insLeuLeuLysLeuLeuLeuLeuLeuGlnLeuGln) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000352 in 1,532,406 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

LHCGR
NM_000233.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.0830

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP5

Variant 2-48755616-G-GGCTGCAGCTGCAGCAGCAGCAGCAGCTTCAGCA is Pathogenic according to our data. Variant chr2-48755616-G-GGCTGCAGCTGCAGCAGCAGCAGCAGCTTCAGCA is described in ClinVar as Pathogenic. ClinVar VariationId is 14405.Status of the report is criteria_provided_single_submitter, 1 stars.

BP3

Nonframeshift variant in repetitive region in NM_000233.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHCGR	NM_000233.4 link	c.55_56insTGCTGAAGCTGCTGCTGCTGCTGCAGCTGCAGC	p.Gln18_Pro19insLeuLeuLysLeuLeuLeuLeuLeuGlnLeuGln	conservative_inframe_insertion	Exon 1 of 11	ENST00000294954.12	NP_000224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12 link	c.55_56insTGCTGAAGCTGCTGCTGCTGCTGCAGCTGCAGC	p.Gln18_Pro19insLeuLeuLysLeuLeuLeuLeuLeuGlnLeuGln	conservative_inframe_insertion	Exon 1 of 11	1	NM_000233.4	ENSP00000294954.6
ENSG00000279956	ENST00000602369.3 link	n.55_56insTGCTGAAGCTGCTGCTGCTGCTGCAGCTGCAGC		non_coding_transcript_exon_variant	Exon 1 of 13	5		ENSP00000473498.1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000151

AC:

AN:

132330

AF XY:

0.0000138

show subpopulations

Gnomad AFR exome

AF:

0.000162

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000248

GnomAD4 exome

AF:

0.0000333

AC:

AN:

1380556

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

681126

show subpopulations

African (AFR)

AF:

0.0000636

AC:

AN:

31426

American (AMR)

AF:

0.00

AC:

AN:

35580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25012

East Asian (EAS)

AF:

0.00

AC:

AN:

35686

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78996

European-Finnish (FIN)

AF:

0.0000269

AC:

AN:

37214

Middle Eastern (MID)

AF:

0.000247

AC:

AN:

4054

European-Non Finnish (NFE)

AF:

0.0000363

AC:

AN:

1075066

Other (OTH)

AF:

0.0000348

AC:

AN:

57522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000527

AC:

AN:

151850

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74188

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41352

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67844

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000481

Hom.:

446

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects LHCGR function (PMID: 9817592). This variant is also known as insLLKLLLLLQ[LQ]. This variant has been observed in individual(s) with autosomal recessive 46, XY leydig cell hypoplasia (PMID: 9817592, 11849253). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant, c.55_56ins33, results in the insertion of 11 amino acid(s) of the LHCGR protein (p.Gln18_Pro19ins11), but otherwise preserves the integrity of the reading frame.

Leydig cell agenesis

Pathogenic:1

Nov 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.083

Mutation Taster

=87/13

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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