rs761108717

Variant names:

• chr19-49047752-C-G
• rs761108717
• NM_033183.3:c.401G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-49047752-C-G
• chr19-49047752-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033183.3(CGB8):​c.401G>C​(p.Arg134Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R134H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB8 NM_033183.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.94
• Publications: 0 publications found

Genes affected

CGB8 (HGNC:16453): (chorionic gonadotropin subunit beta 8) This gene is a member of the glycoprotein hormone beta chain family and encodes the beta 8 subunit of chorionic gonadotropin (CG). Glycoprotein hormones are heterodimers consisting of a common alpha subunit and an unique beta subunit which confers biological specificity. CG is produced by the trophoblastic cells of the placenta and stimulates the ovaries to synthesize the steroids that are essential for the maintenance of pregnancy. The beta subunit of CG is encoded by 6 genes which are arranged in tandem and inverted pairs on chromosome 19q13.3 and contiguous with the luteinizing hormone beta subunit gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05462104).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033183.3. 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
	CGB8	NM_033183.3	MANE Select	c.401G>C	p.Arg134Pro	missense	Exon 3 of 3	NP_149439.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CGB8	ENST00000448456.4	TSL:1 MANE Select	c.401G>C	p.Arg134Pro	missense	Exon 3 of 3	ENSP00000403649.2	P0DN86-1
	CGB8	ENST00000933082.1		c.233G>C	p.Arg78Pro	missense	Exon 2 of 2	ENSP00000603141.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.96e-7 AC: 1 AN: 1437398 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 713626

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32622

American (AMR) AF: 0.00 AC: 0 AN: 42878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39216

South Asian (SAS) AF: 0.00 AC: 0 AN: 83548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4068

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098696

Other (OTH) AF: 0.00 AC: 0 AN: 59188

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.10
DANN	Benign	0.57
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.1	T
PhyloP100		-3.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.11
Sift	Benign	0.22	T
Sift4G	Benign	0.19	T
Vest4		0.038
MutPred		0.18		Gain of glycosylation at S138 (P = 0.0668)
MVP		0.067
MPC		0.0040
ClinPred		0.043	T
GERP RS		-2.9
gMVP		0.027
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs761108717; hg19: chr19-49551009;