7-102097453-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BS1_Supporting BS2

The NM_181552.4(CUX1):c.358G>A(p.Glu120Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,488 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CUX1 NM_181552.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CUX1
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000394 (6/152274) while in subpopulation AFR AF= 0.000145 (6/41476). AF 95% confidence interval is 0.0000628. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUX1	NM_181552.4	c.358G>A	p.Glu120Lys	missense_variant	5/24	ENST00000292535.12
CUX1	NM_001913.5	c.391G>A	p.Glu131Lys	missense_variant	5/23	ENST00000622516.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUX1	ENST00000292535.12	c.358G>A	p.Glu120Lys	missense_variant	5/24	1	NM_181552.4	A2
CUX1	ENST00000622516.6	c.391G>A	p.Glu131Lys	missense_variant	5/23	1	NM_001913.5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152274 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461214 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726880

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152274 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74398

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 23, 2022

Variant summary: CUX1 c.391G>A (p.Glu131Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 146798 control chromosomes, exclusively reported within the African subpopulation at a frequency of 0.00015 (i.e. 6/41156 alleles) in the gnomAD database (v3.1 genomes dataset). To our knowledge, no occurrence of c.391G>A in individuals affected with Global Developmental Delay with or Without Impaired Intellectual Development and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D;D;.;D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.5	N;.;.;N;N;.;N;D;D;N;D;D;N
REVEL	Uncertain	0.33
Sift	Benign	0.19	T;.;.;T;T;.;T;D;D;T;D;D;D
Sift4G	Benign	0.12	T;.;.;T;T;T;D;D;D;D;D;D;D
Polyphen		0.95	P;.;.;P;.;P;.;P;P;P;.;.;.
Vest4		0.81
MutPred		0.40		.;.;.;.;.;.;.;.;Gain of ubiquitination at E120 (P = 0.0104);Gain of ubiquitination at E120 (P = 0.0104);Gain of ubiquitination at E120 (P = 0.0104);Gain of ubiquitination at E120 (P = 0.0104);Gain of ubiquitination at E120 (P = 0.0104);
MVP		0.70
MPC		0.63
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.26
gMVP		0.80

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: rs1042943750; hg19: chr7-101740733;