Genetic Variant NM_002229.3:c.474C>A (chr19-12792245-C-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BS1BS2

The NM_002229.3(JUNB):c.474C>A(p.Ser158Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,510,778 control chromosomes in the GnomAD database, including 731 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 0.021 ( 46 hom., cov: 32)

Exomes 𝑓: 0.029 ( 685 hom. )

Consequence

JUNB
NM_002229.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0990

Publications

11 publications found

Variant links:

Genes affected

JUNB (HGNC:6205): (JunB proto-oncogene, AP-1 transcription factor subunit) Enables sequence-specific double-stranded DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. Part of transcription factor AP-1 complex. Biomarker of Hodgkin's lymphoma and anaplastic large cell lymphoma. [provided by Alliance of Genome Resources, Apr 2022]

JUNB links:

HOOK2 (HGNC:19885): (hook microtubule tethering protein 2) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

HOOK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP7

Synonymous conserved (PhyloP=-0.099 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0215 (3269/152186) while in subpopulation NFE AF = 0.0356 (2420/67956). AF 95% confidence interval is 0.0344. There are 46 homozygotes in GnomAd4. There are 1548 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3269 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUNB	NM_002229.3 link	c.474C>A	p.Ser158Ser	synonymous_variant	Exon 1 of 1	ENST00000302754.6	NP_002220.1	P17275Q5U079
HOOK2	NM_001400043.1 link	c.-209+79G>T		intron_variant	Intron 1 of 21		NP_001386972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JUNB	ENST00000302754.6 link	c.474C>A	p.Ser158Ser	synonymous_variant	Exon 1 of 1	6	NM_002229.3	ENSP00000303315.4	P17275
HOOK2	ENST00000589765.1 link	n.42-18020G>T		intron_variant	Intron 3 of 3	5
HOOK2	ENST00000593143.5 link	n.259+79G>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3272

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0319

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0356

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0182

AC:

2132

AN:

116958

AF XY:

0.0181

show subpopulations

Gnomad AFR exome

AF:

0.00532

Gnomad AMR exome

AF:

0.00851

Gnomad ASJ exome

AF:

0.00840

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0329

Gnomad NFE exome

AF:

0.0310

Gnomad OTH exome

AF:

0.0189

GnomAD4 exome

AF:

0.0292

AC:

39630

AN:

1358592

Hom.:

685

Cov.:

AF XY:

0.0286

AC XY:

19068

AN XY:

666530

show subpopulations

African (AFR)

AF:

0.00429

AC:

130

AN:

30278

American (AMR)

AF:

0.00812

AC:

233

AN:

28678

Ashkenazi Jewish (ASJ)

AF:

0.00819

AC:

181

AN:

22094

East Asian (EAS)

AF:

0.00

AC:

AN:

35826

South Asian (SAS)

AF:

0.00416

AC:

312

AN:

75030

European-Finnish (FIN)

AF:

0.0311

AC:

1443

AN:

46336

Middle Eastern (MID)

AF:

0.00128

AC:

AN:

5462

European-Non Finnish (NFE)

AF:

0.0341

AC:

36143

AN:

1058876

Other (OTH)

AF:

0.0211

AC:

1181

AN:

56012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

2486

4972

7457

9943

12429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1374

2748

4122

5496

6870

<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:

0.0215

AC:

3269

AN:

152186

Hom.:

Cov.:

AF XY:

0.0208

AC XY:

1548

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00578

AC:

240

AN:

41542

American (AMR)

AF:

0.0116

AC:

177

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00951

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00311

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0319

AC:

339

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0356

AC:

2420

AN:

67956

Other (OTH)

AF:

0.0184

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

157

314

470

627

784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0268

Hom.:

Bravo

AF:

0.0187

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.2

(source)

DANN

Benign

0.91

PhyloP100

-0.099

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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