Genetic Variant CGB1:p.Thr50Pro (chr19-49036165-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_033377.2(CGB1):c.148A>C(p.Thr50Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CGB1
NM_033377.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75

Variant links:

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]

CGB1 links:

ENSG00000267335 (HGNC:):

ENSG00000267335 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CGB1	NM_033377.2 link	c.148A>C	p.Thr50Pro	missense_variant	Exon 2 of 3	ENST00000301407.8	NP_203695.2	A6NKQ9-2
CGB1	NM_001382421.1 link	c.112A>C	p.Thr38Pro	missense_variant	Exon 2 of 3		NP_001369350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CGB1	ENST00000301407.8 link	c.148A>C	p.Thr50Pro	missense_variant	Exon 2 of 3	1	NM_033377.2	ENSP00000301407.6	A6NKQ9-2
ENSG00000267335	ENST00000591656.1 link	c.-28+361A>C		intron_variant	Intron 1 of 2	2		ENSP00000466140.1	K7ELM3
ENSG00000267335	ENST00000604577.1 link	c.9+538A>C		intron_variant	Intron 1 of 2	1		ENSP00000474022.1	S4R385
CGB1	ENST00000601167.1 link	c.112A>C	p.Thr38Pro	missense_variant	Exon 2 of 3	5		ENSP00000472896.2	K7ELM3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000427

AC:

AN:

234104

Hom.:

AF XY:

0.00000776

AC XY:

AN XY:

128800

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000925

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1457500

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.148A>C (p.T50P) alteration is located in exon 2 (coding exon 2) of the CGB1 gene. This alteration results from a A to C substitution at nucleotide position 148, causing the threonine (T) at amino acid position 50 to be replaced by a proline (P). 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

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Benign

0.053

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.14

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.5

D;.

REVEL

Uncertain

0.51

Sift

Benign

0.033

D;.

Sift4G

Uncertain

0.023

D;.

Polyphen

1.0

D;.

Vest4

0.52

MutPred

0.83

Loss of sheet (P = 0.0817);.;

MVP

0.78

MPC

2.6

ClinPred

0.95

GERP RS

1.8

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over