Genetic Variant CUX2:p.Arg49Ser (chr12-111214281-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015267.4(CUX2):c.145C>A(p.Arg49Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CUX2
NM_015267.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.38

Publications

2 publications found

Variant links:

Genes affected

CUX2 (HGNC:19347): (cut like homeobox 2) This gene encodes a protein which contains three CUT domains and a homeodomain; both domains are DNA-binding motifs. A similar gene, whose gene product possesses different DNA-binding activities, is located on chromosome on chromosome 7. Two pseudogenes of this gene have been identified on chromosomes 10 and 4. [provided by RefSeq, Jan 2013]

CUX2 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 67
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Lennox-Gastaut syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CUX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06915316).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015267.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX2	NM_015267.4	MANE Select	c.145C>A	p.Arg49Ser	missense	Exon 2 of 22	NP_056082.2	O14529
	CUX2	NM_001370598.1		c.-42C>A		5_prime_UTR	Exon 2 of 22	NP_001357527.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUX2	ENST00000261726.11	TSL:1 MANE Select	c.145C>A	p.Arg49Ser	missense	Exon 2 of 22	ENSP00000261726.6	O14529
CUX2	ENST00000397643.3	TSL:1	c.325C>A	p.Arg109Ser	missense	Exon 3 of 8	ENSP00000380765.3	F5GWR6
CUX2	ENST00000933089.1		c.145C>A	p.Arg49Ser	missense	Exon 2 of 21	ENSP00000603148.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723970

African (AFR)

AF:

0.00

AC:

AN:

33086

American (AMR)

AF:

0.00

AC:

AN:

43864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39346

South Asian (SAS)

AF:

0.00

AC:

AN:

85098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108670

Other (OTH)

AF:

0.00

AC:

AN:

60148

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.049

Eigen

Benign

-0.18

Eigen_PC

Benign

0.097

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.83

M_CAP

Benign

0.0016

MetaRNN

Benign

0.069

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.95

PhyloP100

6.4

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.58

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0090

Vest4

0.28

MutPred

0.33

Gain of phosphorylation at R49 (P = 0.0166)

MVP

0.18

MPC

0.75

ClinPred

0.76

GERP RS

5.6

Varity_R

0.18

gMVP

0.47

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over