19-49023962-A-G

Position:

• chr19-49023962-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000737.5(CGB3):​c.10T>C​(p.Phe4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: CGB3 NM_000737.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.521

Genes affected

CGB3 (HGNC:1886): (chorionic gonadotropin subunit beta 3) This gene is a member of the glycoprotein hormone beta chain family and encodes the beta 3 subunit of chorionic gonadotropin (CG). Glycoprotein hormones are heterodimers consisting of a common alpha subunit and an unique beta subunit which confers biological specificity. CG is produced by the trophoblastic cells of the placenta and stimulates the ovaries to synthesize the steroids that are essential for the maintenance of pregnancy. The beta subunit of CG is encoded by 6 genes which are arranged in tandem and inverted pairs on chromosome 19q13.3 and contiguous with the luteinizing hormone beta subunit gene. [provided by RefSeq, Jul 2008]

ENSG00000267335 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06267941).
• BP6: Variant 19-49023962-A-G is Benign according to our data. Variant chr19-49023962-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2407461.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CGB3	NM_000737.5	c.10T>C	p.Phe4Leu	missense_variant	1/3	ENST00000357383.4	NP_000728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CGB3	ENST00000357383.4	c.10T>C	p.Phe4Leu	missense_variant	1/3	1	NM_000737.5	ENSP00000349954.2
ENSG00000267335	ENST00000591656.1	c.-27-359T>C		intron_variant		2		ENSP00000466140.1
ENSG00000267335	ENST00000604577.1	c.10-359T>C		intron_variant		1		ENSP00000474022.1

Frequencies

GnomAD3 genomes AF: 0.000185 AC: 28 AN: 151728 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 250938 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135626

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000203 AC: 297 AN: 1461196 Hom.: 0 Cov.: 39 AF XY: 0.000188 AC XY: 137 AN XY: 726938

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000232

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000184 AC: 28 AN: 151844 Hom.: 0 Cov.: 28 AF XY: 0.000189 AC XY: 14 AN XY: 74202

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000166

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.0
DANN	Benign	0.21
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00057	N
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.032
Sift	Benign	0.84	T
Sift4G	Benign	1.0	T
Vest4		0.13
MutPred		0.14		Gain of disorder (P = 0.0449);
MVP		0.16
MPC		1.9
ClinPred		0.0088	T
GERP RS		0.065
Varity_R		0.039
gMVP		0.055

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: rs767100833; hg19: chr19-49527219;