chr19-49035648-G-C

Position:

• chr19-49035648-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033377.2(CGB1):​c.430C>G​(p.Pro144Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 27)
• Consequence: CGB1 NM_033377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.122

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07160789).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CGB1	NM_033377.2	c.430C>G	p.Pro144Ala	missense_variant	3/3	ENST00000301407.8	NP_203695.2
CGB1	NM_001382421.1	c.394C>G	p.Pro132Ala	missense_variant	3/3		NP_001369350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CGB1	ENST00000301407.8	c.430C>G	p.Pro144Ala	missense_variant	3/3	1	NM_033377.2	ENSP00000301407.6
ENSG00000267335	ENST00000591656.1	c.-28+878C>G		intron_variant		2		ENSP00000466140.1
ENSG00000267335	ENST00000604577.1	c.9+1055C>G		intron_variant		1		ENSP00000474022.1
CGB1	ENST00000601167.1	c.*5C>G		downstream_gene_variant		5		ENSP00000472896.2

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151340 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000245

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

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151340 Hom.: 0 Cov.: 27 AF XY: 0.0000135 AC XY: 1 AN XY: 73876

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The c.430C>G (p.P144A) alteration is located in exon 3 (coding exon 3) of the CGB1 gene. This alteration results from a C to G substitution at nucleotide position 430, causing the proline (P) at amino acid position 144 to be replaced by an alanine (A). 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	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.35
DANN	Benign	0.69
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.037
Sift	Benign	0.30	T
Sift4G	Benign	0.26	T
Polyphen		0.51	P
Vest4		0.21
MutPred		0.13		Loss of glycosylation at P144 (P = 0.0038);
MVP		0.061
MPC		1.2
ClinPred		0.23	T
GERP RS		-2.9
gMVP		0.062

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: rs755936073; hg19: chr19-49538905;