chr2-48698607-C-T

Variant names:

• chr2-48698607-C-T
• rs6755901
• NM_000233.4:c.866+8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000233.4(LHCGR):​c.866+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.819 in 1,612,146 control chromosomes in the GnomAD database, including 546,775 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50083 hom., cov: 32)
  • Exomes 𝑓: 0.82 (496692 hom.)
• Consequence: LHCGR NM_000233.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006589
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.574
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-48698607-C-T is Benign according to our data. Variant chr2-48698607-C-T is described in ClinVar as Benign. ClinVar VariationId is 255608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.855 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.866+8G>A		splice_region intron	N/A	NP_000224.2
	STON1-GTF2A1L	NM_001198593.2		c.3441+26927C>T		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.866+8G>A		splice_region intron	N/A	ENSP00000294954.6
	ENSG00000279956	ENST00000602369.3	TSL:5	n.*139+8G>A		splice_region intron	N/A	ENSP00000473498.1
	STON1-GTF2A1L	ENST00000402114.6	TSL:2	c.3441+26927C>T		intron	N/A	ENSP00000385701.1

Frequencies

GnomAD3 genomes AF: 0.806 AC: 122490 AN: 152000 Hom.: 50033 Cov.: 32

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.891

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.796

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.811

GnomAD2 exomes AF: 0.752 AC: 188938 AN: 251182 AF XY: 0.764

Gnomad AFR exome AF: 0.864

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.838

Gnomad EAS exome AF: 0.471

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.836

Gnomad OTH exome AF: 0.783

GnomAD4 exome AF: 0.820 AC: 1197202 AN: 1460028 Hom.: 496692 Cov.: 35 AF XY: 0.820 AC XY: 595777 AN XY: 726472

African (AFR) AF: 0.865 AC: 28908 AN: 33438

American (AMR) AF: 0.559 AC: 24994 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.843 AC: 22021 AN: 26126

East Asian (EAS) AF: 0.481 AC: 19103 AN: 39690

South Asian (SAS) AF: 0.799 AC: 68935 AN: 86230

European-Finnish (FIN) AF: 0.699 AC: 37152 AN: 53186

Middle Eastern (MID) AF: 0.781 AC: 4475 AN: 5732

European-Non Finnish (NFE) AF: 0.849 AC: 942815 AN: 1110576

Other (OTH) AF: 0.809 AC: 48799 AN: 60334

GnomAD4 genome AF: 0.806 AC: 122595 AN: 152118 Hom.: 50083 Cov.: 32 AF XY: 0.795 AC XY: 59102 AN XY: 74360

African (AFR) AF: 0.862 AC: 35792 AN: 41514

American (AMR) AF: 0.689 AC: 10542 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 2947 AN: 3472

East Asian (EAS) AF: 0.476 AC: 2451 AN: 5144

South Asian (SAS) AF: 0.797 AC: 3847 AN: 4824

European-Finnish (FIN) AF: 0.692 AC: 7314 AN: 10568

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.838 AC: 56949 AN: 67992

Other (OTH) AF: 0.813 AC: 1716 AN: 2110

Alfa AF: 0.828 Hom.: 99239

Bravo AF: 0.803

Asia WGS AF: 0.702 AC: 2443 AN: 3478

EpiCase AF: 0.844

EpiControl AF: 0.843

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	-0.77
CADD	Benign	7.3
DANN	Benign	0.78
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
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

Other links and lift over

dbSNP: rs6755901; hg19: chr2-48925746; COSMIC: COSV54292706;