12-111214303-T-C

Variant names:

• chr12-111214303-T-C
• rs1881409057
• NM_015267.4:c.167T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015267.4(CUX2):​c.167T>C​(p.Val56Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000212 in 1,417,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CUX2 NM_015267.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUX2	NM_015267.4	c.167T>C	p.Val56Ala	missense_variant	Exon 2 of 22	ENST00000261726.11	NP_056082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUX2	ENST00000261726.11	c.167T>C	p.Val56Ala	missense_variant	Exon 2 of 22	1	NM_015267.4	ENSP00000261726.6
CUX2	ENST00000397643.3	c.347T>C	p.Val116Ala	missense_variant	Exon 3 of 8	1		ENSP00000380765.3
CUX2	ENST00000551604.2	n.3T>C		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1417644 Hom.: 0 Cov.: 23 AF XY: 0.00000283 AC XY: 2 AN XY: 707098

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: 0.0000241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 67 Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.167T>C(p.Val56Ala) variant in CUX2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Val56Ala variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Val at position 56 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Val56Ala in CUX2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.86	L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.17
Sift	Benign	0.24	T;T
Sift4G	Benign	0.096	T;T
Polyphen		1.0	D;D
Vest4		0.47
MutPred		0.21		Gain of ubiquitination at K53 (P = 0.0645);.;
MVP		0.56
MPC		0.83
ClinPred		0.81	D
GERP RS		5.6
Varity_R		0.18
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs1881409057; hg19: chr12-111652107;