2-48688732-A-G

Variant names:

• chr2-48688732-A-G
• rs11125179
• NM_000233.4:c.1065T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000233.4(LHCGR):​c.1065T>C​(p.Asp355Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 1,613,476 control chromosomes in the GnomAD database, including 282,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22710 hom., cov: 31)
  • Exomes 𝑓: 0.59 (259603 hom.)
• Consequence: LHCGR NM_000233.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.456
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-48688732-A-G is Benign according to our data. Variant chr2-48688732-A-G is described in ClinVar as Benign. ClinVar VariationId is 255607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.456 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 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.1065T>C	p.Asp355Asp	synonymous	Exon 11 of 11	NP_000224.2
	STON1-GTF2A1L	NM_001198593.2		c.3441+17052A>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.1065T>C	p.Asp355Asp	synonymous	Exon 11 of 11	ENSP00000294954.6
	ENSG00000279956	ENST00000602369.3	TSL:5	n.*220+5492T>C		intron	N/A	ENSP00000473498.1
	LHCGR	ENST00000405626.5	TSL:5	c.984T>C	p.Asp328Asp	synonymous	Exon 10 of 10	ENSP00000386033.1

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80031 AN: 151860 Hom.: 22709 Cov.: 31

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.569

GnomAD2 exomes AF: 0.614 AC: 154217 AN: 251310 AF XY: 0.612

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.708

Gnomad ASJ exome AF: 0.669

Gnomad EAS exome AF: 0.930

Gnomad FIN exome AF: 0.574

Gnomad NFE exome AF: 0.584

Gnomad OTH exome AF: 0.616

GnomAD4 exome AF: 0.591 AC: 863015 AN: 1461496 Hom.: 259603 Cov.: 45 AF XY: 0.591 AC XY: 429728 AN XY: 727068

African (AFR) AF: 0.306 AC: 10238 AN: 33476

American (AMR) AF: 0.698 AC: 31226 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 17357 AN: 26134

East Asian (EAS) AF: 0.936 AC: 37144 AN: 39700

South Asian (SAS) AF: 0.600 AC: 51711 AN: 86252

European-Finnish (FIN) AF: 0.573 AC: 30627 AN: 53418

Middle Eastern (MID) AF: 0.695 AC: 4010 AN: 5766

European-Non Finnish (NFE) AF: 0.580 AC: 644231 AN: 1111640

Other (OTH) AF: 0.604 AC: 36471 AN: 60386

GnomAD4 genome AF: 0.527 AC: 80067 AN: 151980 Hom.: 22710 Cov.: 31 AF XY: 0.534 AC XY: 39678 AN XY: 74278

African (AFR) AF: 0.313 AC: 12970 AN: 41438

American (AMR) AF: 0.634 AC: 9678 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2235 AN: 3472

East Asian (EAS) AF: 0.929 AC: 4797 AN: 5164

South Asian (SAS) AF: 0.606 AC: 2921 AN: 4818

European-Finnish (FIN) AF: 0.579 AC: 6118 AN: 10566

Middle Eastern (MID) AF: 0.648 AC: 188 AN: 290

European-Non Finnish (NFE) AF: 0.581 AC: 39513 AN: 67956

Other (OTH) AF: 0.569 AC: 1198 AN: 2106

Alfa AF: 0.572 Hom.: 49585

Bravo AF: 0.526

Asia WGS AF: 0.700 AC: 2437 AN: 3478

EpiCase AF: 0.590

EpiControl AF: 0.594

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	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	-0.54
CADD	Benign	3.3
DANN	Benign	0.74
PhyloP100		0.46
Mutation Taster		=99/1	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: rs11125179; hg19: chr2-48915871; COSMIC: COSV108111124;