2-48713541-C-T

Variant names:

• chr2-48713541-C-T
• rs6737881
• NM_000233.4:c.605+445G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000233.4(LHCGR):​c.605+445G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 152,046 control chromosomes in the GnomAD database, including 40,524 homozygotes. 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: 𝑓 0.73 (40524 hom., cov: 31)
• Consequence: LHCGR NM_000233.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.02
• Publications: 1 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHCGR	NM_000233.4	c.605+445G>A		intron_variant	Intron 7 of 10	ENST00000294954.12	NP_000224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12	c.605+445G>A		intron_variant	Intron 7 of 10	1	NM_000233.4	ENSP00000294954.6
ENSG00000279956	ENST00000602369.3	n.530+445G>A		intron_variant	Intron 6 of 12	5		ENSP00000473498.1

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110512 AN: 151928 Hom.: 40506 Cov.: 31

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.704

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.727 AC: 110569 AN: 152046 Hom.: 40524 Cov.: 31 AF XY: 0.722 AC XY: 53666 AN XY: 74346

African (AFR) AF: 0.767 AC: 31785 AN: 41462

American (AMR) AF: 0.699 AC: 10669 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2374 AN: 3470

East Asian (EAS) AF: 0.771 AC: 3985 AN: 5166

South Asian (SAS) AF: 0.536 AC: 2585 AN: 4820

European-Finnish (FIN) AF: 0.701 AC: 7424 AN: 10584

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.726 AC: 49344 AN: 67960

Other (OTH) AF: 0.701 AC: 1477 AN: 2106

Alfa AF: 0.726 Hom.: 17449

Bravo AF: 0.734

Asia WGS AF: 0.635 AC: 2212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.096
DANN	Benign	0.53
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -21

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

Other links and lift over

dbSNP: rs6737881; hg19: chr2-48940680;