Genetic Variant CBY2:p.Leu42Val (chr13-45702823-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152719.3(CBY2):c.124C>G(p.Leu42Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CBY2
NM_152719.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0290

Variant links:

Genes affected

CBY2 (HGNC:30720): (chibby family member 2) Enables identical protein binding activity. Predicted to be located in cytoplasmic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

CBY2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050149173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBY2	NM_152719.3 link	c.124C>G	p.Leu42Val	missense_variant	Exon 2 of 3	ENST00000310521.6	NP_689932.1	Q8NA61-1A0A140VJV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CBY2	ENST00000310521.6 link	c.124C>G	p.Leu42Val	missense_variant	Exon 2 of 3	1	NM_152719.3	ENSP00000309189.1	Q8NA61-1
CBY2	ENST00000610924.1 link	c.-34+308C>G		intron_variant	Intron 1 of 2	5		ENSP00000480148.1	Q8NA61-2
CBY2	ENST00000533564.1 link	c.75+358C>G		intron_variant	Intron 1 of 1	2		ENSP00000435230.1	E9PLB4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251406

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135880

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727202

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.124C>G (p.L42V) alteration is located in exon 2 (coding exon 2) of the SPERT gene. This alteration results from a C to G substitution at nucleotide position 124, causing the leucine (L) at amino acid position 42 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

0.084

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.49

M_CAP

Benign

0.013

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.59

REVEL

Benign

0.046

Sift

Benign

0.47

Sift4G

Benign

0.15

Polyphen

0.015

Vest4

0.17

MutPred

0.11

Gain of sheet (P = 0.0827);

MVP

0.51

MPC

0.34

ClinPred

0.068

GERP RS

2.7

Varity_R

0.063

gMVP

0.14

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