2-48687476-C-G

Position:

• chr2-48687476-C-G

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.*221G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 443,248 control chromosomes in the GnomAD database, including 9,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2902 hom., cov: 32)
  • Exomes 𝑓: 0.20 (6225 hom.)
• Consequence: LHCGR NM_000233.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.199

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]

STON1-GTF2A1L (HGNC:):

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=-0.94).
• BP6: Variant 2-48687476-C-G is Benign according to our data. Variant chr2-48687476-C-G is described in ClinVar as [Benign]. Clinvar id is 336454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHCGR	NM_000233.4	c.*221G>C		3_prime_UTR_variant	11/11	ENST00000294954.12
STON1-GTF2A1L	NM_001198593.2	c.3441+15796C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHCGR	ENST00000294954.12	c.*221G>C		3_prime_UTR_variant	11/11	1	NM_000233.4	A2
GTF2A1L	ENST00000508440.1	c.276+15796C>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28291 AN: 151988 Hom.: 2899 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0660

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.178

GnomAD4 exome AF: 0.196 AC: 57189 AN: 291142 Hom.: 6225 Cov.: 3 AF XY: 0.198 AC XY: 29570 AN XY: 149408

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.0589

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.186 AC: 28312 AN: 152106 Hom.: 2902 Cov.: 32 AF XY: 0.188 AC XY: 13974 AN XY: 74328

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.0657

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.181

Alfa AF: 0.111 Hom.: 195

Bravo AF: 0.176

Asia WGS AF: 0.197 AC: 683 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
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	-0.94
CADD	Benign	0.47
DANN	Benign	0.46

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: rs62137532; hg19: chr2-48914615;