7-102070411-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181552.4(CUX1):c.262G>A(p.Val88Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,608,414 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (19 hom.)
• Consequence: CUX1 NM_181552.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.23

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CUX1
• BP4: Computational evidence support a benign effect (MetaRNN=0.011179209).
• BP6: Variant 7-102070411-G-A is Benign according to our data. Variant chr7-102070411-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 709065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00212 (323/152238) while in subpopulation NFE AF= 0.0037 (252/68024). AF 95% confidence interval is 0.00333. There are 1 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 321 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUX1	NM_181552.4	c.262G>A	p.Val88Ile	missense_variant	4/24	ENST00000292535.12
CUX1	NM_001913.5	c.295G>A	p.Val99Ile	missense_variant	4/23	ENST00000622516.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUX1	ENST00000292535.12	c.262G>A	p.Val88Ile	missense_variant	4/24	1	NM_181552.4	A2
CUX1	ENST00000622516.6	c.295G>A	p.Val99Ile	missense_variant	4/23	1	NM_001913.5

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 321 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00203 AC: 494 AN: 243800 Hom.: 1 AF XY: 0.00218 AC XY: 288 AN XY: 132174

Gnomad AFR exome AF: 0.000704

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00162

Gnomad FIN exome AF: 0.000421

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00381 AC: 5554 AN: 1456176 Hom.: 19 Cov.: 31 AF XY: 0.00377 AC XY: 2731 AN XY: 724384

Gnomad4 AFR exome AF: 0.000516

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.000301

Gnomad4 NFE exome AF: 0.00460

Gnomad4 OTH exome AF: 0.00342

GnomAD4 genome AF: 0.00212 AC: 323 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74438

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00370

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00204 Hom.: 1

Bravo AF: 0.00206

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CUX1: BS1 -

CUX1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;D;D;.;D;D;D;D;D;.;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.42	N;.;.;N;N;.;N;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.28	T;.;.;T;T;.;T;D;T;D;D;D;D;D
Sift4G	Benign	0.43	T;.;.;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.67	P;.;.;P;.;P;.;D;.;D;D;.;.;.
Vest4		0.40
MVP		0.24
MPC		0.45
ClinPred		0.042	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.65

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: rs148322402; hg19: chr7-101713691; COSMIC: COSV52911957;