Genetic Variant NCL:c.1448-121G>A (chr2-231457245-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005381.3(NCL):c.1448-121G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 1,348,226 control chromosomes in the GnomAD database, including 125,039 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 0.46 ( 16303 hom., cov: 32)

Exomes 𝑓: 0.42 ( 108736 hom. )

Consequence

NCL
NM_005381.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.65

Publications

23 publications found

Variant links:

Genes affected

NCL (HGNC:7667): (nucleolin) Nucleolin (NCL), a eukaryotic nucleolar phosphoprotein, is involved in the synthesis and maturation of ribosomes. It is located mainly in dense fibrillar regions of the nucleolus. Human NCL gene consists of 14 exons with 13 introns and spans approximately 11kb. The intron 11 of the NCL gene encodes a small nucleolar RNA, termed U20. [provided by RefSeq, Jul 2008]

NCL 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=-0.79).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCL	NM_005381.3 link	c.1448-121G>A		intron_variant	Intron 9 of 13	ENST00000322723.9	NP_005372.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCL	ENST00000322723.9 link	c.1448-121G>A		intron_variant	Intron 9 of 13	2	NM_005381.3	ENSP00000318195.4

Frequencies

GnomAD3 genomes

AF:

0.460

AC:

69884

AN:

151920

Hom.:

16290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.548

Gnomad AMI

AF:

0.447

Gnomad AMR

AF:

0.438

Gnomad ASJ

AF:

0.528

Gnomad EAS

AF:

0.517

Gnomad SAS

AF:

0.415

Gnomad FIN

AF:

0.397

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.417

Gnomad OTH

AF:

0.450

GnomAD2 exomes

AF:

0.447

AC:

99427

AN:

222642

AF XY:

0.444

show subpopulations

Gnomad AFR exome

AF:

0.558

Gnomad AMR exome

AF:

0.456

Gnomad ASJ exome

AF:

0.529

Gnomad EAS exome

AF:

0.519

Gnomad FIN exome

AF:

0.413

Gnomad NFE exome

AF:

0.424

Gnomad OTH exome

AF:

0.441

GnomAD4 exome

AF:

0.423

AC:

505572

AN:

1196188

Hom.:

108736

Cov.:

AF XY:

0.423

AC XY:

256637

AN XY:

606274

show subpopulations

African (AFR)

AF:

0.542

AC:

15300

AN:

28218

American (AMR)

AF:

0.453

AC:

18627

AN:

41118

Ashkenazi Jewish (ASJ)

AF:

0.523

AC:

12627

AN:

24158

East Asian (EAS)

AF:

0.568

AC:

21688

AN:

38156

South Asian (SAS)

AF:

0.411

AC:

32381

AN:

78870

European-Finnish (FIN)

AF:

0.420

AC:

21937

AN:

52200

Middle Eastern (MID)

AF:

0.412

AC:

2167

AN:

5266

European-Non Finnish (NFE)

AF:

0.409

AC:

358654

AN:

876708

Other (OTH)

AF:

0.431

AC:

22191

AN:

51494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

14688

29375

44063

58750

73438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10086

20172

30258

40344

50430

<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:

0.460

AC:

69941

AN:

152038

Hom.:

16303

Cov.:

AF XY:

0.459

AC XY:

34083

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.548

AC:

22708

AN:

41434

American (AMR)

AF:

0.438

AC:

6692

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.528

AC:

1832

AN:

3470

East Asian (EAS)

AF:

0.518

AC:

2685

AN:

5180

South Asian (SAS)

AF:

0.414

AC:

1998

AN:

4826

European-Finnish (FIN)

AF:

0.397

AC:

4195

AN:

10568

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.417

AC:

28357

AN:

67968

Other (OTH)

AF:

0.449

AC:

946

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1938

3876

5814

7752

9690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

636

1272

1908

2544

3180

<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:

0.438

Hom.:

35155

Bravo

AF:

0.467

Asia WGS

AF:

0.461

AC:

1601

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.45

(source)

DANN

Benign

0.60

PhyloP100

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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