19-49047752-C-T

Position:

• chr19-49047752-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The ENST00000448456.4(CGB8):​c.401G>A​(p.Arg134His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R134P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00011 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB8 ENST00000448456.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.94

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043058097).
• BP6: Variant 19-49047752-C-T is Benign according to our data. Variant chr19-49047752-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3143904.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CGB8	NM_033183.3	c.401G>A	p.Arg134His	missense_variant	3/3	ENST00000448456.4	NP_149439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CGB8	ENST00000448456.4	c.401G>A	p.Arg134His	missense_variant	3/3	1	NM_033183.3	ENSP00000403649	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 14 AN: 150622 Hom.: 0 Cov.: 24 FAILED QC

Gnomad AFR AF: 0.0000247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 10 AN: 58644 Hom.: 0 AF XY: 0.000101 AC XY: 3 AN XY: 29634

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00445

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000506

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000108 AC: 155 AN: 1437378 Hom.: 1 Cov.: 37 AF XY: 0.000121 AC XY: 86 AN XY: 713612

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.0000233

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000373

Gnomad4 OTH exome AF: 0.000270

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000929 AC: 14 AN: 150740 Hom.: 0 Cov.: 24 AF XY: 0.0000407 AC XY: 3 AN XY: 73660

Gnomad4 AFR AF: 0.0000247

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000337 Hom.: 0

ExAC AF: 0.000114 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.025
DANN	Benign	0.72
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.054
Sift	Benign	0.59	T
Sift4G	Benign	0.13	T
Vest4		0.040
MutPred		0.15		Gain of glycosylation at S138 (P = 0.0837);
MVP		0.048
MPC		0.0042
ClinPred		0.022	T
GERP RS		-2.9
gMVP		0.022

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761108717; hg19: chr19-49551009;