19-49032570-C-T

Position:

• chr19-49032570-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033378.2(CGB2):​c.76C>T​(p.Arg26Trp) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB2 NM_033378.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.533

Genes affected

CGB2 (HGNC:16722): (chorionic gonadotropin subunit beta 2) 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 CGB2 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 163 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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027944326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CGB2	NM_033378.2	c.76C>T	p.Arg26Trp	missense_variant	2/3	ENST00000359342.7	NP_203696.2
CGB2	NM_001319065.2	c.40C>T	p.Arg14Trp	missense_variant	2/3		NP_001305994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CGB2	ENST00000359342.7	c.76C>T	p.Arg26Trp	missense_variant	2/3	1	NM_033378.2	ENSP00000352295.6
CGB2	ENST00000474913.1	c.40C>T	p.Arg14Trp	missense_variant	2/3	1		ENSP00000471177.1
ENSG00000267335	ENST00000591656.1	c.-28+3956G>A		intron_variant		2		ENSP00000466140.1
ENSG00000267335	ENST00000604577.1	c.9+4133G>A		intron_variant		1		ENSP00000474022.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 233 AN: 144128 Hom.: 0 Cov.: 24 FAILED QC

Gnomad AFR AF: 0.00570

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000684

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000230

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000452

Gnomad OTH AF: 0.00356

GnomAD3 exomes AF: 0.000283 AC: 49 AN: 173446 Hom.: 0 AF XY: 0.000240 AC XY: 23 AN XY: 95658

Gnomad AFR exome AF: 0.00410

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000156

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000261

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000162 AC: 226 AN: 1392438 Hom.: 0 Cov.: 31 AF XY: 0.000145 AC XY: 100 AN XY: 688314

Gnomad4 AFR exome AF: 0.00471

Gnomad4 AMR exome AF: 0.000263

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000172

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000222

Gnomad4 OTH exome AF: 0.000517

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00166 AC: 239 AN: 144244 Hom.: 0 Cov.: 24 AF XY: 0.00167 AC XY: 117 AN XY: 70074

Gnomad4 AFR AF: 0.00584

Gnomad4 AMR AF: 0.000683

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000230

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000453

Gnomad4 OTH AF: 0.00352

Alfa AF: 0.00202 Hom.: 0

ExAC AF: 0.000290 AC: 33

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

Dec 07, 2021

The c.76C>T (p.R26W) alteration is located in exon 2 (coding exon 2) of the CGB2 gene. This alteration results from a C to T substitution at nucleotide position 76, causing the arginine (R) at amino acid position 26 to be replaced by a tryptophan (W). 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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.84
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.96	.;N
REVEL	Benign	0.13
Sift	Benign	0.19	.;T
Sift4G	Benign	0.19	T;T
Vest4		0.15
MVP		0.50
MPC		1.8
ClinPred		0.013	T
GERP RS		0.71
Varity_R		0.050
gMVP		0.34

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

Other links and lift over

dbSNP: rs753143101; hg19: chr19-49535827; COSMIC: COSV100031532; COSMIC: COSV100031532;