rs10495960

Positions:

• chr2-48732893-G-A
• chr2-48732893-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000233.4(LHCGR):​c.162-1595C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 534,206 control chromosomes in the GnomAD database, including 9,169 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 0.15 (2177 hom., cov: 32)
  • Exomes 𝑓: 0.17 (6992 hom.)
• Consequence: LHCGR NM_000233.4 intron
• Scores: Splicing: ADA: 0.00005694
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.363

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]

STON1-GTF2A1L (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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019029975).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHCGR	NM_000233.4	c.162-1595C>T		intron_variant		ENST00000294954.12	NP_000224.2
STON1-GTF2A1L	NM_001198593.2	c.3442-43387G>A		intron_variant			NP_001185522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12	c.162-1595C>T		intron_variant		1	NM_000233.4	ENSP00000294954	A2

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22373 AN: 152024 Hom.: 2171 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.0608

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.146

GnomAD3 exomes AF: 0.185 AC: 45551 AN: 246534 Hom.: 5381 AF XY: 0.174 AC XY: 23351 AN XY: 133980

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.320

Gnomad SAS exome AF: 0.0549

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.170 AC: 64815 AN: 382064 Hom.: 6992 Cov.: 0 AF XY: 0.157 AC XY: 34247 AN XY: 217498

Gnomad4 AFR exome AF: 0.0371

Gnomad4 AMR exome AF: 0.343

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.0557

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.147 AC: 22380 AN: 152142 Hom.: 2177 Cov.: 32 AF XY: 0.149 AC XY: 11054 AN XY: 74362

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.252

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.0603

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.143

Alfa AF: 0.164 Hom.: 3831

Bravo AF: 0.151

TwinsUK AF: 0.169 AC: 627

ALSPAC AF: 0.187 AC: 720

ESP6500AA AF: 0.0379 AC: 140

ESP6500EA AF: 0.162 AC: 1323

ExAC AF: 0.173 AC: 20930

Asia WGS AF: 0.160 AC: 554 AN: 3478

EpiCase AF: 0.162

EpiControl AF: 0.164

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.8
DANN	Benign	0.63
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PROVEAN	Benign	0.030	N
REVEL	Benign	0.0050
Sift	Benign	0.033	D
Sift4G	Benign	0.067	T
ClinPred		0.0021	T
GERP RS		0.031

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs10495960; hg19: chr2-48960032; COSMIC: COSV54297584;