19-49033133-C-A

Position:

• chr19-49033133-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033378.2(CGB2):​c.404C>A​(p.Ala135Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 142,566 control chromosomes in the GnomAD database, including 6,977 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (6977 hom., cov: 21)
  • Exomes 𝑓: 0.30 (76216 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB2 NM_033378.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0830

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003944099).
• BP6: Variant 19-49033133-C-A is Benign according to our data. Variant chr19-49033133-C-A is described in ClinVar as [Benign]. Clinvar id is 769979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CGB2	NM_033378.2	c.404C>A	p.Ala135Asp	missense_variant	3/3	ENST00000359342.7	NP_203696.2
CGB2	NM_001319065.2	c.368C>A	p.Ala123Asp	missense_variant	3/3		NP_001305994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CGB2	ENST00000359342.7	c.404C>A	p.Ala135Asp	missense_variant	3/3	1	NM_033378.2	ENSP00000352295	P1
CGB2	ENST00000474913.1	c.368C>A	p.Ala123Asp	missense_variant	3/3	1		ENSP00000471177

Frequencies

GnomAD3 genomes AF: 0.314 AC: 44693 AN: 142462 Hom.: 6976 Cov.: 21

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.320

GnomAD3 exomes AF: 0.227 AC: 43920 AN: 193402 Hom.: 8475 AF XY: 0.222 AC XY: 23076 AN XY: 104152

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.108

Gnomad SAS exome AF: 0.188

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.246

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.297 AC: 368694 AN: 1242236 Hom.: 76216 Cov.: 47 AF XY: 0.297 AC XY: 184847 AN XY: 621948

Gnomad4 AFR exome AF: 0.291

Gnomad4 AMR exome AF: 0.334

Gnomad4 ASJ exome AF: 0.314

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.262

Gnomad4 FIN exome AF: 0.270

Gnomad4 NFE exome AF: 0.305

Gnomad4 OTH exome AF: 0.297

GnomAD4 genome AF: 0.314 AC: 44720 AN: 142566 Hom.: 6977 Cov.: 21 AF XY: 0.310 AC XY: 21503 AN XY: 69426

Gnomad4 AFR AF: 0.309

Gnomad4 AMR AF: 0.377

Gnomad4 ASJ AF: 0.346

Gnomad4 EAS AF: 0.150

Gnomad4 SAS AF: 0.274

Gnomad4 FIN AF: 0.252

Gnomad4 NFE AF: 0.325

Gnomad4 OTH AF: 0.317

Alfa AF: 0.293 Hom.: 1202

ExAC AF: 0.270 AC: 32658

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.47
DANN	Benign	0.48
DEOGEN2	Pathogenic	0.81	.;D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.30	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	.;N
REVEL	Benign	0.022
Sift	Benign	0.41	.;T
Sift4G	Benign	0.14	T;T
Vest4		0.14
MPC		3.4
ClinPred		0.0013	T
GERP RS		0.72
Varity_R		0.27
gMVP		0.057

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: rs62126039; hg19: chr19-49536390; COSMIC: COSV56818904; COSMIC: COSV56818904;