2-48755616-GGCTGCA-GGCTGCAGCTGCA

Variant names:

• chr2-48755616-G-GGCTGCA
• rs71245621
• NM_000233.4:c.50_55dupTGCAGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_000233.4(LHCGR):​c.50_55dupTGCAGC​(p.Leu17_Gln18dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,531,600 control chromosomes in the GnomAD database, including 47,276 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3903 hom., cov: 25)
  • Exomes 𝑓: 0.25 (43373 hom.)
• Consequence: LHCGR NM_000233.4 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: 0.0830
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000233.4
• BP6: Variant 2-48755616-G-GGCTGCA is Benign according to our data. Variant chr2-48755616-G-GGCTGCA is described in ClinVar as Benign. ClinVar VariationId is 336471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000233.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHCGR	NM_000233.4	MANE Select	c.50_55dupTGCAGC	p.Leu17_Gln18dup	conservative_inframe_insertion	Exon 1 of 11	NP_000224.2	P22888-1
	STON1-GTF2A1L	NM_001198593.2		c.3442-20661_3442-20656dupTGCAGC		intron	N/A	NP_001185522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHCGR	ENST00000294954.12	TSL:1 MANE Select	c.50_55dupTGCAGC	p.Leu17_Gln18dup	conservative_inframe_insertion	Exon 1 of 11	ENSP00000294954.6	P22888-1
	ENSG00000279956	ENST00000602369.3	TSL:5	n.50_55dupTGCAGC		non_coding_transcript_exon	Exon 1 of 13	ENSP00000473498.1	R4GN57
	LHCGR	ENST00000405626.5	TSL:5	c.50_55dupTGCAGC	p.Leu17_Gln18dup	conservative_inframe_insertion	Exon 1 of 10	ENSP00000386033.1	E7ENI1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33267 AN: 151786 Hom.: 3909 Cov.: 25

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.241

GnomAD2 exomes AF: 0.190 AC: 25112 AN: 132330 AF XY: 0.189

Gnomad AFR exome AF: 0.176

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.0114

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.246 AC: 339426 AN: 1379704 Hom.: 43373 Cov.: 34 AF XY: 0.242 AC XY: 164931 AN XY: 680642

African (AFR) AF: 0.179 AC: 5608 AN: 31380

American (AMR) AF: 0.135 AC: 4794 AN: 35526

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7308 AN: 24990

East Asian (EAS) AF: 0.00841 AC: 300 AN: 35686

South Asian (SAS) AF: 0.131 AC: 10313 AN: 78936

European-Finnish (FIN) AF: 0.191 AC: 7102 AN: 37190

Middle Eastern (MID) AF: 0.286 AC: 1157 AN: 4050

European-Non Finnish (NFE) AF: 0.269 AC: 289229 AN: 1074474

Other (OTH) AF: 0.237 AC: 13615 AN: 57472

GnomAD4 genome AF: 0.219 AC: 33261 AN: 151896 Hom.: 3903 Cov.: 25 AF XY: 0.210 AC XY: 15607 AN XY: 74268

African (AFR) AF: 0.187 AC: 7743 AN: 41450

American (AMR) AF: 0.185 AC: 2831 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1041 AN: 3464

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5164

South Asian (SAS) AF: 0.119 AC: 573 AN: 4828

European-Finnish (FIN) AF: 0.188 AC: 1993 AN: 10596

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.267 AC: 18112 AN: 67808

Other (OTH) AF: 0.238 AC: 502 AN: 2108

Alfa AF: 0.173 Hom.: 446

Asia WGS AF: 0.0840 AC: 295 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Gonadotropin-independent familial sexual precocity (1)
-	-	1	Hypergonadotropic hypogonadism (1)
-	-	1	Leydig cell agenesis (1)
1	-	-	Luteinizing hormone/choriogonadotropin receptor, lq variant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.083
Mutation Taster		=87/13	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs71245621; hg19: chr2-48982755; COSMIC: COSV54295979; COSMIC: COSV54295979;