12-111214273-T-C

Position:

• chr12-111214273-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_015267.4(CUX2):​c.137T>C​(p.Ile46Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,458,008 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: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CUX2 NM_015267.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4195302).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUX2	NM_015267.4	c.137T>C	p.Ile46Thr	missense_variant	2/22	ENST00000261726.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUX2	ENST00000261726.11	c.137T>C	p.Ile46Thr	missense_variant	2/22	1	NM_015267.4	P1
CUX2	ENST00000397643.3	c.317T>C	p.Ile106Thr	missense_variant	3/8	1
CUX2	ENST00000551604.2			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000203 AC: 5 AN: 245854 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133510

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000599

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1458008 Hom.: 0 Cov.: 30 AF XY: 0.00000965 AC XY: 7 AN XY: 725274

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000680

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000991

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000598

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 67 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.62	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.048	D;D
Polyphen		0.92	P;D
Vest4		0.69
MutPred		0.22		Gain of phosphorylation at I46 (P = 0.0178);.;
MVP		0.39
MPC		1.6
ClinPred		0.75	D
GERP RS		5.6
Varity_R		0.47
gMVP		0.25

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: rs371927310; hg19: chr12-111652077;