7-102104390-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_181552.4(CUX1):c.461A>C(p.Lys154Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: CUX1 NM_181552.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

Genes affected

CUX1 (HGNC:2557): (cut like homeobox 1) The protein encoded by this gene is a member of the homeodomain family of DNA binding proteins. It may regulate gene expression, morphogenesis, and differentiation and it may also play a role in the cell cycle progession. Several alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CUX1
• BP4: Computational evidence support a benign effect (MetaRNN=0.30798563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUX1	NM_181552.4	c.461A>C	p.Lys154Thr	missense_variant	6/24	ENST00000292535.12
CUX1	NM_001913.5	c.494A>C	p.Lys165Thr	missense_variant	6/23	ENST00000622516.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUX1	ENST00000292535.12	c.461A>C	p.Lys154Thr	missense_variant	6/24	1	NM_181552.4	A2
CUX1	ENST00000622516.6	c.494A>C	p.Lys165Thr	missense_variant	6/23	1	NM_001913.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

CUX1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2022

The CUX1 c.494A>C variant is predicted to result in the amino acid substitution p.Lys165Thr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D;D;D;.;D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.2	N;.;.;N;N;.;N;N;D;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.054	T;.;.;T;T;.;T;T;D;T;T;T;T;T
Sift4G	Benign	0.14	T;.;.;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.95	P;.;.;D;.;D;.;P;.;P;P;.;.;.
Vest4		0.62
MutPred		0.21		.;.;.;.;.;.;.;.;.;Loss of ubiquitination at K154 (P = 0.0039);Loss of ubiquitination at K154 (P = 0.0039);Loss of ubiquitination at K154 (P = 0.0039);Loss of ubiquitination at K154 (P = 0.0039);Loss of ubiquitination at K154 (P = 0.0039);
MVP		0.21
MPC		0.67
ClinPred		0.91	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-101747670;