rs6755901

Positions:

• chr2-48698607-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000233.4(LHCGR):​c.866+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.819 in 1,612,146 control chromosomes in the GnomAD database, including 546,775 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50083 hom., cov: 32)
  • Exomes 𝑓: 0.82 (496692 hom.)
• Consequence: LHCGR NM_000233.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006589
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.574

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-48698607-C-T is Benign according to our data. Variant chr2-48698607-C-T is described in ClinVar as [Benign]. Clinvar id is 255608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48698607-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHCGR	NM_000233.4	c.866+8G>A		splice_region_variant, intron_variant		ENST00000294954.12	NP_000224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12	c.866+8G>A		splice_region_variant, intron_variant		1	NM_000233.4	ENSP00000294954.6
ENSG00000279956	ENST00000602369.3	n.*139+8G>A		splice_region_variant, intron_variant		5		ENSP00000473498.1

Frequencies

GnomAD3 genomes AF: 0.806 AC: 122490 AN: 152000 Hom.: 50033 Cov.: 32

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.891

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.796

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.811

GnomAD3 exomes AF: 0.752 AC: 188938 AN: 251182 Hom.: 73578 AF XY: 0.764 AC XY: 103721 AN XY: 135782

Gnomad AFR exome AF: 0.864

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.838

Gnomad EAS exome AF: 0.471

Gnomad SAS exome AF: 0.798

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.836

Gnomad OTH exome AF: 0.783

GnomAD4 exome AF: 0.820 AC: 1197202 AN: 1460028 Hom.: 496692 Cov.: 35 AF XY: 0.820 AC XY: 595777 AN XY: 726472

Gnomad4 AFR exome AF: 0.865

Gnomad4 AMR exome AF: 0.559

Gnomad4 ASJ exome AF: 0.843

Gnomad4 EAS exome AF: 0.481

Gnomad4 SAS exome AF: 0.799

Gnomad4 FIN exome AF: 0.699

Gnomad4 NFE exome AF: 0.849

Gnomad4 OTH exome AF: 0.809

GnomAD4 genome AF: 0.806 AC: 122595 AN: 152118 Hom.: 50083 Cov.: 32 AF XY: 0.795 AC XY: 59102 AN XY: 74360

Gnomad4 AFR AF: 0.862

Gnomad4 AMR AF: 0.689

Gnomad4 ASJ AF: 0.849

Gnomad4 EAS AF: 0.476

Gnomad4 SAS AF: 0.797

Gnomad4 FIN AF: 0.692

Gnomad4 NFE AF: 0.838

Gnomad4 OTH AF: 0.813

Alfa AF: 0.830 Hom.: 81148

Bravo AF: 0.803

Asia WGS AF: 0.702 AC: 2443 AN: 3478

EpiCase AF: 0.844

EpiControl AF: 0.843

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypergonadotropic hypogonadism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Leydig cell agenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.77
CADD	Benign	7.3
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0
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: rs6755901; hg19: chr2-48925746; COSMIC: COSV54292706;