19-49035798-C-T

Variant names:

• chr19-49035798-C-T
• rs775053454
• NM_033377.2:c.280G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_033377.2(CGB1):​c.280G>A​(p.Val94Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. V94G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000097 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB1 NM_033377.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98
• Publications: 0 publications found

Genes affected

CGB1 (HGNC:16721): (chorionic gonadotropin subunit beta 1) The beta subunit of chorionic gonadotropin (CGB) is encoded by six highly homologous and structurally similar genes that are arranged in tandem and inverted pairs on chromosome 19q13.3, and contiguous with the luteinizing hormone beta (LHB) subunit gene. The CGB genes are primarily distinguished by differences in the 5' untranscribed region. This gene was originally thought to be one of the two pseudogenes (CGB1 and CGB2) of CGB subunit, however, detection of CGB1 and CGB2 transcripts in vivo, and their presence on the polysomes, suggested that these transcripts are translated. To date, a protein product corresponding to CGB1 has not been isolated. The deduced sequence of the hypothetical protein of 132 aa does not share any similarity with that of functional CGB subunits (PMID:8954017). However, a 155 aa protein, translated from a different frame, is about the same size, and shares 98% identity with other CGB subunits. [provided by RefSeq, Jul 2008]

ENSG00000267335 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033377.2. 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
	CGB1	NM_033377.2	MANE Select	c.280G>A	p.Val94Met	missense	Exon 3 of 3	NP_203695.2	A6NKQ9-2
	CGB1	NM_001382421.1		c.244G>A	p.Val82Met	missense	Exon 3 of 3	NP_001369350.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CGB1	ENST00000301407.8	TSL:1 MANE Select	c.280G>A	p.Val94Met	missense	Exon 3 of 3	ENSP00000301407.6	A6NKQ9-2
	ENSG00000267335	ENST00000591656.1	TSL:2	c.-28+728G>A		intron	N/A	ENSP00000466140.1	K7ELM3
	ENSG00000267335	ENST00000604577.1	TSL:1	c.9+905G>A		intron	N/A	ENSP00000474022.1	S4R385

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148154 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000255

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000470 AC: 1 AN: 212558 AF XY: 0.00000854

Gnomad AFR exome AF: 0.0000898

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000969 AC: 14 AN: 1445004 Hom.: 0 Cov.: 33 AF XY: 0.0000125 AC XY: 9 AN XY: 717304

African (AFR) AF: 0.0000307 AC: 1 AN: 32566

American (AMR) AF: 0.00 AC: 0 AN: 43404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 39390

South Asian (SAS) AF: 0.00 AC: 0 AN: 85782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4096

European-Non Finnish (NFE) AF: 0.00000998 AC: 11 AN: 1102392

Other (OTH) AF: 0.0000336 AC: 2 AN: 59516

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000675 AC: 1 AN: 148154 Hom.: 0 Cov.: 26 AF XY: 0.0000139 AC XY: 1 AN XY: 72140

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

African (AFR) AF: 0.0000255 AC: 1 AN: 39264

American (AMR) AF: 0.00 AC: 0 AN: 14898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67272

Other (OTH) AF: 0.00 AC: 0 AN: 1998

⚠️ 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

ExAC AF: 0.00000864 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.072
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.63	T
PhyloP100		2.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.71		Gain of methylation at R92 (P = 0.122)
MVP		0.64
MPC		2.3
ClinPred		0.96	D
GERP RS		1.8
gMVP		0.13
Mutation Taster		=97/3	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: rs775053454; hg19: chr19-49539055;