Genetic Variant CBLL1:p.Asp2Asn (chr7-107744167-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_024814.4(CBLL1):c.4G>A(p.Asp2Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000193 in 1,555,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CBLL1
NM_024814.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.35

Variant links:

Genes affected

CBLL1 (HGNC:21225): (Cbl proto-oncogene like 1) This gene encodes an E3 ubiquitin-ligase for the E-cadherin complex and mediates its ubiquitination, endocytosis, and degradation in the lysosomes. The encoded protein contains a RING-finger domain and is also thought to have a role in control of cell proliferation. A related pseudogene has been identified on chromosome X. Alternative splicing results in a non-coding transcript variant. [provided by RefSeq, Aug 2011]

CBLL1 links:

CBLL1-AS1 (HGNC:55571): (CBLL1 antisense RNA 1)

CBLL1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40291342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLL1	NM_024814.4 link	c.4G>A	p.Asp2Asn	missense_variant	Exon 1 of 6	ENST00000440859.8	NP_079090.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLL1	ENST00000440859.8 link	c.4G>A	p.Asp2Asn	missense_variant	Exon 1 of 6	1	NM_024814.4	ENSP00000401277.2		Q75N03-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1402926

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692626

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.25e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4G>A (p.D2N) alteration is located in exon 1 (coding exon 1) of the CBLL1 gene. This alteration results from a G to A substitution at nucleotide position 4, causing the aspartic acid (D) at amino acid position 2 to be replaced by an asparagine (N). 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

0.47

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

T;.;T

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;L;.

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.84

N;N;.

REVEL

Benign

0.20

Sift

Benign

0.047

D;D;.

Sift4G

Benign

0.23

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.43

MutPred

0.41

Loss of stability (P = 0.1454);Loss of stability (P = 0.1454);Loss of stability (P = 0.1454);

MVP

0.55

MPC

0.63

ClinPred

0.96

GERP RS

5.4

Varity_R

0.22

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over