2-48729373-A-G

Variant names:

• chr2-48729373-A-G
• rs11897846
• NM_000233.4:c.234-146T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000233.4(LHCGR):​c.234-146T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 703,872 control chromosomes in the GnomAD database, including 41,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11559 hom., cov: 32)
  • Exomes 𝑓: 0.31 (29494 hom.)
• Consequence: LHCGR NM_000233.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.49

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-48729373-A-G is Benign according to our data. Variant chr2-48729373-A-G is described in ClinVar as [Benign]. Clinvar id is 1272187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHCGR	NM_000233.4	c.234-146T>C		intron_variant	Intron 2 of 10	ENST00000294954.12	NP_000224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHCGR	ENST00000294954.12	c.234-146T>C		intron_variant	Intron 2 of 10	1	NM_000233.4	ENSP00000294954.6
ENSG00000279956	ENST00000602369.3	n.233+1854T>C		intron_variant	Intron 2 of 12	5		ENSP00000473498.1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56028 AN: 151906 Hom.: 11545 Cov.: 32

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.600

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.306 AC: 168853 AN: 551848 Hom.: 29494 AF XY: 0.298 AC XY: 88940 AN XY: 298604

Gnomad4 AFR exome AF: 0.518

Gnomad4 AMR exome AF: 0.564

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.539

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.346

Gnomad4 NFE exome AF: 0.260

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.369 AC: 56075 AN: 152024 Hom.: 11559 Cov.: 32 AF XY: 0.375 AC XY: 27844 AN XY: 74324

Gnomad4 AFR AF: 0.505

Gnomad4 AMR AF: 0.468

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.600

Gnomad4 SAS AF: 0.268

Gnomad4 FIN AF: 0.349

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.334

Alfa AF: 0.276 Hom.: 12676

Bravo AF: 0.391

Asia WGS AF: 0.410 AC: 1423 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.33
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs11897846; hg19: chr2-48956512;