Genetic Variant CUX2:p.Ala85Val (chr12-111263792-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4BP6_ModerateBS2

The NM_015267.4(CUX2):c.254C>T(p.Ala85Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000366 in 1,613,998 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

CUX2
NM_015267.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 5.39

Publications

4 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3674647).

BP6

Variant 12-111263792-C-T is Benign according to our data. Variant chr12-111263792-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3026003.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 24 AD gene.

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.254C>T	p.Ala85Val	missense	Exon 4 of 22	NP_056082.2	O14529
	CUX2	NM_001370598.1		c.68C>T	p.Ala23Val	missense	Exon 4 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.254C>T	p.Ala85Val	missense	Exon 4 of 22	ENSP00000261726.6	O14529
CUX2	ENST00000397643.3	TSL:1	c.434C>T	p.Ala145Val	missense	Exon 5 of 8	ENSP00000380765.3	F5GWR6
CUX2	ENST00000933089.1		c.206C>T	p.Ala69Val	missense	Exon 3 of 21	ENSP00000603148.1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000441

AC:

AN:

249576

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111964

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000158

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.000483

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000127

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.000523

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000414

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

CUX2-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.022

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.0

PhyloP100

5.4

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.24

Sift

Uncertain

0.022

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.91

MVP

0.57

MPC

0.71

ClinPred

0.32

GERP RS

5.0

Varity_R

0.42

gMVP

0.50

Mutation Taster

=90/10

polymorphism

(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

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over