chr2-48732893-G-C

Variant names:

• chr2-48732893-G-C
• rs10495960
• NM_000233.4:c.162-1595C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000233.4(LHCGR):​c.162-1595C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000262 in 382,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: LHCGR NM_000233.4 intron
• Scores: Splicing: ADA: 0.00009908
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.363
• Publications: 0 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:):

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]

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0715082).

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.162-1595C>G		intron	N/A	NP_000224.2	P22888-1
	STON1-GTF2A1L	NM_001198593.2		c.3442-43387G>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.162-1595C>G		intron	N/A	ENSP00000294954.6	P22888-1
	ENSG00000279956	ENST00000602369.3	TSL:5	n.162-1595C>G		intron	N/A	ENSP00000473498.1	R4GN57
	GTF2A1L	ENST00000508440.1	TSL:2	c.277G>C	p.Ala93Pro	missense splice_region	Exon 3 of 3	ENSP00000421474.1	H0Y8M0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000262 AC: 1 AN: 382198 Hom.: 0 Cov.: 0 AF XY: 0.00000460 AC XY: 1 AN XY: 217560

African (AFR) AF: 0.00 AC: 0 AN: 10506

American (AMR) AF: 0.00 AC: 0 AN: 36282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11744

East Asian (EAS) AF: 0.00 AC: 0 AN: 13174

South Asian (SAS) AF: 0.00 AC: 0 AN: 66738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2854

European-Non Finnish (NFE) AF: 0.00000521 AC: 1 AN: 191894

Other (OTH) AF: 0.00 AC: 0 AN: 16704

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	10
DANN	Benign	0.61
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.36
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.013
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.020	D
MutPred		0.38		Gain of disorder (P = 0.0076)
MVP		0.055
ClinPred		0.065	T
GERP RS		0.031
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000099
dbscSNV1_RF	Benign	0.018
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: rs10495960; hg19: chr2-48960032;