Genetic Variant NM_033043.2:c.15+164T>G (chr19-49044388-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_033043.2(CGB5):c.15+164T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 148,390 control chromosomes in the GnomAD database, including 10,781 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.36 ( 10781 hom., cov: 28)

Exomes 𝑓: 0.34 ( 49978 hom. )

Failed GnomAD Quality Control

Consequence

CGB5
NM_033043.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.42

Publications

2 publications found

Variant links:

Genes affected

CGB5 (HGNC:16452): (chorionic gonadotropin subunit beta 5) This gene is a member of the glycoprotein hormone beta chain family and encodes the beta 5 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]

CGB5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CGB5	NM_033043.2 link	c.15+164T>G		intron_variant	Intron 1 of 2	ENST00000301408.7	NP_149032.1	P0DN86-1A0A0F7RQP8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CGB5	ENST00000301408.7 link	c.15+164T>G		intron_variant	Intron 1 of 2	1	NM_033043.2	ENSP00000301408.5		P0DN86-1

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

53131

AN:

148282

Hom.:

10757

Cov.:

show subpopulations

Gnomad AFR

AF:

0.438

Gnomad AMI

AF:

0.340

Gnomad AMR

AF:

0.400

Gnomad ASJ

AF:

0.366

Gnomad EAS

AF:

0.149

Gnomad SAS

AF:

0.315

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.339

Gnomad OTH

AF:

0.362

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.340

AC:

282886

AN:

832288

Hom.:

49978

Cov.:

AF XY:

0.340

AC XY:

130855

AN XY:

384368

show subpopulations

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

African (AFR)

AF:

0.441

AC:

6831

AN:

15504

American (AMR)

AF:

0.367

AC:

361

AN:

984

Ashkenazi Jewish (ASJ)

AF:

0.348

AC:

1791

AN:

5152

East Asian (EAS)

AF:

0.134

AC:

488

AN:

3630

South Asian (SAS)

AF:

0.312

AC:

5132

AN:

16448

European-Finnish (FIN)

AF:

0.268

AC:

AN:

276

Middle Eastern (MID)

AF:

0.309

AC:

500

AN:

1620

European-Non Finnish (NFE)

AF:

0.340

AC:

258573

AN:

761408

Other (OTH)

AF:

0.335

AC:

9136

AN:

27266

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.367

Heterozygous variant carriers

14677

29355

44032

58710

73387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11384

22768

34152

45536

56920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.358

AC:

53191

AN:

148390

Hom.:

10781

Cov.:

AF XY:

0.354

AC XY:

25699

AN XY:

72504

show subpopulations

African (AFR)

AF:

0.439

AC:

16871

AN:

38438

American (AMR)

AF:

0.400

AC:

6038

AN:

15082

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

1268

AN:

3460

East Asian (EAS)

AF:

0.149

AC:

763

AN:

5128

South Asian (SAS)

AF:

0.315

AC:

1502

AN:

4772

European-Finnish (FIN)

AF:

0.254

AC:

2666

AN:

10510

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.339

AC:

22932

AN:

67728

Other (OTH)

AF:

0.358

AC:

743

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1477

2953

4430

5906

7383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.183

Hom.:

355

Bravo

AF:

0.372

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.25

(source)

DANN

Benign

0.17

PhyloP100

-3.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over