chr2-48694299-T-C

Variant names:

• chr2-48694299-T-C
• rs12470652
• NM_000233.4:c.872A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000233.4(LHCGR):​c.872A>G​(p.Asn291Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,591,022 control chromosomes in the GnomAD database, including 2,122 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (139 hom., cov: 33)
  • Exomes 𝑓: 0.049 (1983 hom.)
• Consequence: LHCGR NM_000233.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.13
• Publications: 32 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]

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

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.16259 (below the threshold of 3.09). Trascript score misZ: -0.035144 (below the threshold of 3.09). GenCC associations: The gene is linked to Leydig cell hypoplasia, type 1, familial male-limited precocious puberty.
• BP4: Computational evidence support a benign effect (MetaRNN=0.002693206).
• BP6: Variant 2-48694299-T-C is Benign according to our data. Variant chr2-48694299-T-C is described in ClinVar as Benign. ClinVar VariationId is 138116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0544 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.872A>G	p.Asn291Ser	missense	Exon 10 of 11	NP_000224.2	P22888-1
	STON1-GTF2A1L	NM_001198593.2		c.3441+22619T>C		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.872A>G	p.Asn291Ser	missense	Exon 10 of 11	ENSP00000294954.6	P22888-1
	ENSG00000279956	ENST00000602369.3	TSL:5	n.*145A>G		non_coding_transcript_exon	Exon 9 of 13	ENSP00000473498.1	R4GN57
	ENSG00000279956	ENST00000602369.3	TSL:5	n.*145A>G		3_prime_UTR	Exon 9 of 13	ENSP00000473498.1	R4GN57

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5707 AN: 152168 Hom.: 139 Cov.: 33

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0657

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0559

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0380 AC: 8953 AN: 235680 AF XY: 0.0386

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0420

Gnomad EAS exome AF: 0.000171

Gnomad FIN exome AF: 0.0652

Gnomad NFE exome AF: 0.0555

Gnomad OTH exome AF: 0.0417

GnomAD4 exome AF: 0.0488 AC: 70217 AN: 1438736 Hom.: 1983 Cov.: 28 AF XY: 0.0481 AC XY: 34435 AN XY: 715502

African (AFR) AF: 0.00981 AC: 326 AN: 33220

American (AMR) AF: 0.0195 AC: 855 AN: 43796

Ashkenazi Jewish (ASJ) AF: 0.0413 AC: 1069 AN: 25884

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39462

South Asian (SAS) AF: 0.0129 AC: 1094 AN: 84542

European-Finnish (FIN) AF: 0.0628 AC: 3322 AN: 52874

Middle Eastern (MID) AF: 0.0105 AC: 60 AN: 5738

European-Non Finnish (NFE) AF: 0.0558 AC: 60971 AN: 1093616

Other (OTH) AF: 0.0422 AC: 2514 AN: 59604

GnomAD4 genome AF: 0.0375 AC: 5705 AN: 152286 Hom.: 139 Cov.: 33 AF XY: 0.0364 AC XY: 2711 AN XY: 74458

African (AFR) AF: 0.0121 AC: 505 AN: 41578

American (AMR) AF: 0.0258 AC: 394 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 134 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4824

European-Finnish (FIN) AF: 0.0657 AC: 698 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0559 AC: 3802 AN: 67992

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0471 Hom.: 532

Bravo AF: 0.0339

TwinsUK AF: 0.0545 AC: 202

ALSPAC AF: 0.0651 AC: 251

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.0546 AC: 469

ExAC AF: 0.0365 AC: 4422

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Gonadotropin-independent familial sexual precocity (1)
-	-	1	Hypergonadotropic hypogonadism (1)
-	-	1	Leydig cell agenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.086	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0027	T
MetaSVM	Uncertain	0.026	D
MutationAssessor	Benign	1.3	L
PhyloP100		3.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.19	N
REVEL	Uncertain	0.32
Sift	Benign	0.66	T
Sift4G	Benign	0.86	T
Polyphen		1.0	D
Vest4		0.22
MPC		0.11
ClinPred		0.029	T
GERP RS		5.4
Varity_R		0.093
gMVP		0.34
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12470652; hg19: chr2-48921438; COSMIC: COSV54299337;