chr19-49054536-C-T

Variant names:

• chr19-49054536-C-T
• rs745743591
• NM_001385261.1:c.253G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001385261.1(CGB7):​c.253G>A​(p.Glu85Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 19)
  • Exomes 𝑓: 0.0000055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CGB7 NM_001385261.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.669
• Publications: 0 publications found

Genes affected

CGB7 (HGNC:16451): (chorionic gonadotropin subunit beta 7) This gene is a member of the glycoprotein hormone beta chain family and encodes the beta 7 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2316392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CGB7	NM_001385261.1	c.253G>A	p.Glu85Lys	missense_variant	Exon 5 of 5	ENST00000684222.1	NP_001372190.1
CGB7	NM_033142.2	c.253G>A	p.Glu85Lys	missense_variant	Exon 5 of 5		NP_149133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CGB7	ENST00000684222.1	c.253G>A	p.Glu85Lys	missense_variant	Exon 5 of 5		NM_001385261.1	ENSP00000507822.1
CGB7	ENST00000596965.5	c.253G>A	p.Glu85Lys	missense_variant	Exon 5 of 5	2		ENSP00000469076.1
CGB7	ENST00000597853.5	c.253G>A	p.Glu85Lys	missense_variant	Exon 5 of 5	2		ENSP00000470813.1

Frequencies

GnomAD3 genomes AF: 0.0000603 AC: 8 AN: 132738 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000217

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 63918 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000554 AC: 7 AN: 1262478 Hom.: 0 Cov.: 23 AF XY: 0.00000796 AC XY: 5 AN XY: 628388

African (AFR) AF: 0.0000971 AC: 3 AN: 30888

American (AMR) AF: 0.0000268 AC: 1 AN: 37302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23878

East Asian (EAS) AF: 0.00 AC: 0 AN: 36420

South Asian (SAS) AF: 0.00 AC: 0 AN: 77884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3796

European-Non Finnish (NFE) AF: 0.00000210 AC: 2 AN: 953766

Other (OTH) AF: 0.0000187 AC: 1 AN: 53422

GnomAD4 genome AF: 0.0000602 AC: 8 AN: 132844 Hom.: 0 Cov.: 19 AF XY: 0.0000946 AC XY: 6 AN XY: 63442

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000217 AC: 8 AN: 36904

American (AMR) AF: 0.00 AC: 0 AN: 13198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3206

East Asian (EAS) AF: 0.00 AC: 0 AN: 4530

South Asian (SAS) AF: 0.00 AC: 0 AN: 3604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60152

Other (OTH) AF: 0.00 AC: 0 AN: 1722

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000227 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253G>A (p.E85K) alteration is located in exon 3 (coding exon 3) of the CGB7 gene. This alteration results from a G to A substitution at nucleotide position 253, causing the glutamic acid (E) at amino acid position 85 to be replaced by a lysine (K). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.83	T;.;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.30	T
PhyloP100		0.67
PROVEAN	Benign	-1.5	N;.;.
REVEL	Benign	0.25
Sift	Benign	0.38	T;.;.
Sift4G	Benign	0.56	T;T;T
Vest4		0.14
MVP		0.47
MPC		1.4
ClinPred		0.60	D
GERP RS		1.8
Varity_R		0.045
gMVP		0.27
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs745743591; hg19: chr19-49557793;