2-48687476-C-G

Variant names:

• chr2-48687476-C-G
• rs62137532
• NM_000233.4:c.*221G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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 -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 VariationId 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.

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.*221G>C		3_prime_UTR	Exon 11 of 11	NP_000224.2	P22888-1
	STON1-GTF2A1L	NM_001198593.2		c.3441+15796C>G		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.*221G>C		3_prime_UTR	Exon 11 of 11	ENSP00000294954.6	P22888-1
	ENSG00000279956	ENST00000602369.3	TSL:5	n.*220+6748G>C		intron	N/A	ENSP00000473498.1	R4GN57
	LHCGR	ENST00000913067.1		c.*221G>C		3_prime_UTR	Exon 7 of 7	ENSP00000583126.1

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

African (AFR) AF: 0.120 AC: 1053 AN: 8768

American (AMR) AF: 0.186 AC: 2085 AN: 11182

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 1359 AN: 9990

East Asian (EAS) AF: 0.0589 AC: 1429 AN: 24262

South Asian (SAS) AF: 0.242 AC: 3565 AN: 14756

European-Finnish (FIN) AF: 0.236 AC: 4692 AN: 19908

Middle Eastern (MID) AF: 0.136 AC: 187 AN: 1378

European-Non Finnish (NFE) AF: 0.215 AC: 39288 AN: 182588

Other (OTH) AF: 0.193 AC: 3531 AN: 18310

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

African (AFR) AF: 0.121 AC: 5032 AN: 41524

American (AMR) AF: 0.195 AC: 2985 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3468

East Asian (EAS) AF: 0.0657 AC: 341 AN: 5188

South Asian (SAS) AF: 0.254 AC: 1222 AN: 4818

European-Finnish (FIN) AF: 0.239 AC: 2519 AN: 10552

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15031 AN: 67966

Other (OTH) AF: 0.181 AC: 383 AN: 2112

Alfa AF: 0.111 Hom.: 195

Bravo AF: 0.176

Asia WGS AF: 0.197 AC: 683 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.47
DANN	Benign	0.46
PhyloP100		0.20
Mutation Taster		=100/0	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: rs62137532; hg19: chr2-48914615;