19-49047726-C-T

Variant names:

• chr19-49047726-C-T
• rs1280203641
• NM_033183.3:c.427G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033183.3(CGB8):​c.427G>A​(p.Ala143Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A143S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0000062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB8 NM_033183.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.253
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061376512).

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.427G>A	p.Ala143Thr	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.427G>A	p.Ala143Thr	missense	Exon 3 of 3	ENSP00000403649.2	P0DN86-1
	CGB8	ENST00000933082.1		c.259G>A	p.Ala87Thr	missense	Exon 2 of 2	ENSP00000603141.1

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150932 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000619 AC: 9 AN: 1455052 Hom.: 0 Cov.: 38 AF XY: 0.00000829 AC XY: 6 AN XY: 723450

⚠️ 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: 33168

American (AMR) AF: 0.0000450 AC: 2 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25736

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109270

Other (OTH) AF: 0.00 AC: 0 AN: 59992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000782357), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000662 AC: 1 AN: 151050 Hom.: 0 Cov.: 24 AF XY: 0.0000135 AC XY: 1 AN XY: 73806

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

African (AFR) AF: 0.00 AC: 0 AN: 40724

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67900

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.1
DANN	Benign	0.90
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.00097	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.25
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.078
Sift	Benign	0.14	T
Sift4G	Benign	0.18	T
Vest4		0.042
MutPred		0.19		Gain of phosphorylation at A143 (P = 8e-04)
MVP		0.13
MPC		0.0050
ClinPred		0.046	T
GERP RS		1.5
gMVP		0.015
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs1280203641; hg19: chr19-49550983;