chr19-49023530-C-T

Variant names:

• chr19-49023530-C-T
• rs200012583
• NM_000737.5:c.89G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000737.5(CGB3):​c.89G>A​(p.Arg30His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 9)
  • Exomes 𝑓: 0.00053 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB3 NM_000737.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0120

Genes affected

CGB3 (HGNC:1886): (chorionic gonadotropin subunit beta 3) This gene is a member of the glycoprotein hormone beta chain family and encodes the beta 3 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]

ENSG00000267335 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35607034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CGB3	NM_000737.5	c.89G>A	p.Arg30His	missense_variant	Exon 2 of 3	ENST00000357383.4	NP_000728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CGB3	ENST00000357383.4	c.89G>A	p.Arg30His	missense_variant	Exon 2 of 3	1	NM_000737.5	ENSP00000349954.2
ENSG00000267335	ENST00000591656.1	c.47G>A	p.Arg16His	missense_variant	Exon 2 of 3	2		ENSP00000466140.1
ENSG00000267335	ENST00000604577.1	c.83G>A	p.Arg28His	missense_variant	Exon 2 of 3	1		ENSP00000474022.1

Frequencies

GnomAD3 genomes AF: 0.000757 AC: 54 AN: 71348 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000178

Gnomad ASJ AF: 0.000494

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000527

Gnomad FIN AF: 0.000235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000312

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000533 AC: 264 AN: 494926 Hom.: 0 Cov.: 5 AF XY: 0.000553 AC XY: 142 AN XY: 256822

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.000273

Gnomad4 ASJ exome AF: 0.000292

Gnomad4 EAS exome AF: 0.0000648

Gnomad4 SAS exome AF: 0.000490

Gnomad4 FIN exome AF: 0.000429

Gnomad4 NFE exome AF: 0.000590

Gnomad4 OTH exome AF: 0.000478

GnomAD4 genome AF: 0.000756 AC: 54 AN: 71402 Hom.: 0 Cov.: 9 AF XY: 0.000734 AC XY: 24 AN XY: 32686

Gnomad4 AFR AF: 0.00191

Gnomad4 AMR AF: 0.000178

Gnomad4 ASJ AF: 0.000494

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000531

Gnomad4 FIN AF: 0.000235

Gnomad4 NFE AF: 0.000312

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00354 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.89G>A (p.R30H) alteration is located in exon 2 (coding exon 2) of the CGB3 gene. This alteration results from a G to A substitution at nucleotide position 89, causing the arginine (R) at amino acid position 30 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	10
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.80	.;.;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.36	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.23	N;.;.
REVEL	Benign	0.28
Sift	Benign	0.20	T;.;.
Sift4G	Benign	0.37	T;.;.
Vest4		0.096
MutPred		0.17		Loss of glycosylation at P27 (P = 0.08);.;.;
MVP		0.84
MPC		2.2
ClinPred		0.044	T
GERP RS		0.74
Varity_R		0.083
gMVP		0.095

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: rs200012583; hg19: chr19-49526787; COSMIC: COSV105261681; COSMIC: COSV105261681;