chr19-49047726-C-A

Variant names:

• chr19-49047726-C-A
• rs1280203641
• NM_033183.3:c.427G>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.427G>T​(p.Ala143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 151,050 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB8 NM_033183.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050955713).

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>T	p.Ala143Ser	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>T	p.Ala143Ser	missense	Exon 3 of 3	ENSP00000403649.2	P0DN86-1
	CGB8	ENST00000933082.1		c.259G>T	p.Ala87Ser	missense	Exon 2 of 2	ENSP00000603141.1

Frequencies

GnomAD3 genomes AF: 0.0000265 AC: 4 AN: 150932 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000440 AC: 3 AN: 68136 AF XY: 0.0000885

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000302 AC: 44 AN: 1455062 Hom.: 0 Cov.: 38 AF XY: 0.0000290 AC XY: 21 AN XY: 723454

⚠️ 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: 0.00 AC: 0 AN: 44494

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

East Asian (EAS) AF: 0.0000757 AC: 3 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: 0.0000334 AC: 37 AN: 1109270

Other (OTH) AF: 0.0000500 AC: 3 AN: 59992

⚠️ 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 AF: 0.0000265 AC: 4 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: 40722

American (AMR) AF: 0.0000656 AC: 1 AN: 15236

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: 0.0000442 AC: 3 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 = 0.00000000000213107), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	0.070
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.6
DANN	Benign	0.86
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.00095	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.25
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.037
Sift	Benign	0.42	T
Sift4G	Benign	0.49	T
Vest4		0.078
MutPred		0.19		Gain of phosphorylation at A143 (P = 5e-04)
MVP		0.15
MPC		0.0050
ClinPred		0.019	T
GERP RS		1.5
gMVP		0.016
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1280203641; hg19: chr19-49550983;