2-48688732-A-G

Variant names:

• chr2-48688732-A-G
• rs11125179
• NM_000233.4:c.1065T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.456

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]

ENSG00000279956 (HGNC:):

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]

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 255607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48688732-A-G is described in Lovd as [Benign].
• 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	c.1065T>C	p.Asp355Asp	synonymous_variant	Exon 11 of 11	ENST00000294954.12	NP_000224.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80031 AN: 151860 Hom.: 22709 Cov.: 31

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

GnomAD3 exomes AF: 0.614 AC: 154217 AN: 251310 Hom.: 49432 AF XY: 0.612 AC XY: 83133 AN XY: 135816

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 SAS exome AF: 0.600

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.: 45 AF XY: 0.591 AC XY: 429728 AN XY: 727068

Gnomad4 AFR exome AF: 0.306

Gnomad4 AMR exome AF: 0.698

Gnomad4 ASJ exome AF: 0.664

Gnomad4 EAS exome AF: 0.936

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.573

Gnomad4 NFE exome AF: 0.580

Gnomad4 OTH exome AF: 0.604

GnomAD4 genome AF: 0.527 AC: 80067 AN: 151980 Hom.: 22710 Cov.: 31 AF XY: 0.534 AC XY: 39678 AN XY: 74278

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.634

Gnomad4 ASJ AF: 0.644

Gnomad4 EAS AF: 0.929

Gnomad4 SAS AF: 0.606

Gnomad4 FIN AF: 0.579

Gnomad4 NFE AF: 0.581

Gnomad4 OTH AF: 0.569

Alfa AF: 0.578 Hom.: 41091

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

Submissions by phenotype

not specified Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

- -

-

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

- -

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

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
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.3
DANN	Benign	0.74

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

LitVar

Other links and lift over

dbSNP: rs11125179; hg19: chr2-48915871;