rs4073366

Positions:

• chr2-48755483-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.161+28G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,431,042 control chromosomes in the GnomAD database, including 21,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2275 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19170 hom.)
• Consequence: LHCGR NM_000233.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0630

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-48755483-C-G is Benign according to our data. Variant chr2-48755483-C-G is described in ClinVar as [Benign]. Clinvar id is 1278671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-48755483-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHCGR	NM_000233.4	c.161+28G>C		intron_variant		ENST00000294954.12	NP_000224.2
STON1-GTF2A1L	NM_001198593.2	c.3442-20797C>G		intron_variant			NP_001185522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12	c.161+28G>C		intron_variant		1	NM_000233.4	ENSP00000294954	A2

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24357 AN: 152056 Hom.: 2267 Cov.: 32

Gnomad AFR AF: 0.0979

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.0586

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.155

GnomAD3 exomes AF: 0.187 AC: 26433 AN: 141026 Hom.: 3204 AF XY: 0.174 AC XY: 13232 AN XY: 75932

Gnomad AFR exome AF: 0.0930

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.337

Gnomad SAS exome AF: 0.0551

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.165 AC: 210580 AN: 1278868 Hom.: 19170 Cov.: 18 AF XY: 0.161 AC XY: 102423 AN XY: 634988

Gnomad4 AFR exome AF: 0.0912

Gnomad4 AMR exome AF: 0.330

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.289

Gnomad4 SAS exome AF: 0.0539

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.160 AC: 24376 AN: 152174 Hom.: 2275 Cov.: 32 AF XY: 0.162 AC XY: 12022 AN XY: 74386

Gnomad4 AFR AF: 0.0978

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.324

Gnomad4 SAS AF: 0.0581

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.153

Alfa AF: 0.158 Hom.: 406

Bravo AF: 0.167

Asia WGS AF: 0.169 AC: 586 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.34

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: rs4073366; hg19: chr2-48982622; COSMIC: COSV54301735;