Genetic Variant NBEAL1:p.Ile520Val (chr2-203107797-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001378026.1(NBEAL1):c.1558A>G(p.Ile520Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000753 in 1,554,324 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 1 hom. )

Consequence

NBEAL1
NM_001378026.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94

Variant links:

Genes affected

NBEAL1 (HGNC:20681): (neurobeachin like 1) Predicted to enable protein kinase binding activity. Predicted to be involved in protein localization. Predicted to be active in cytosol and membrane. [provided by Alliance of Genome Resources, Apr 2022]

NBEAL1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012443453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBEAL1	NM_001378026.1 link	c.1558A>G	p.Ile520Val	missense_variant	Exon 14 of 56	ENST00000683969.1	NP_001364955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBEAL1	ENST00000683969.1 link	c.1558A>G	p.Ile520Val	missense_variant	Exon 14 of 56		NM_001378026.1	ENSP00000508055.1		A0A804HKS6

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000174

AC:

AN:

160618

AF XY:

0.000153

show subpopulations

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:

0.00141

Gnomad NFE exome

AF:

0.0000319

Gnomad OTH exome

AF:

0.000445

GnomAD4 exome

AF:

0.0000713

AC:

100

AN:

1402198

Hom.:

Cov.:

AF XY:

0.0000694

AC XY:

AN XY:

691606

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32096

American (AMR)

AF:

0.00

AC:

AN:

35714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25184

East Asian (EAS)

AF:

0.00

AC:

AN:

36620

South Asian (SAS)

AF:

0.00

AC:

AN:

79496

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

49488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00000463

AC:

AN:

1079716

Other (OTH)

AF:

0.000172

AC:

AN:

58182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000112

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000503

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000291

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 11, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1471A>G (p.I491V) alteration is located in exon 13 (coding exon 12) of the NBEAL1 gene. This alteration results from a A to G substitution at nucleotide position 1471, causing the isoleucine (I) at amino acid position 491 to be replaced by a valine (V). 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

Benign

0.087

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0018

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.059

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.74

M_CAP

Benign

0.0088

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

1.9

PrimateAI

Benign

0.39

PROVEAN

Benign

0.14

REVEL

Benign

0.082

Sift

Benign

0.40

Sift4G

Benign

0.22

Polyphen

0.0

Vest4

0.11

MVP

0.47

MPC

0.090

ClinPred

0.027

GERP RS

3.5

Varity_R

0.032

gMVP

0.070

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Loading publications...

2-203107797-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over