chr7-101916213-G-C

Variant names:

• chr7-101916213-G-C
• rs748511869
• NM_181552.4:c.129G>C

Variant summary

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

The NM_181552.4(CUX1):​c.129G>C​(p.Lys43Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000295 in 1,457,338 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: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: CUX1 NM_181552.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28218988).
• BS2: High AC in GnomAdExome4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUX1	NM_181552.4	c.129G>C	p.Lys43Asn	missense_variant	Exon 2 of 24	ENST00000292535.12	NP_853530.2
CUX1	NM_001913.5	c.162G>C	p.Lys54Asn	missense_variant	Exon 2 of 23	ENST00000622516.6	NP_001904.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUX1	ENST00000292535.12	c.129G>C	p.Lys43Asn	missense_variant	Exon 2 of 24	1	NM_181552.4	ENSP00000292535.7
CUX1	ENST00000622516.6	c.162G>C	p.Lys54Asn	missense_variant	Exon 2 of 23	1	NM_001913.5	ENSP00000484760.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251480 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000295 AC: 43 AN: 1457338 Hom.: 0 Cov.: 27 AF XY: 0.0000221 AC XY: 16 AN XY: 725338

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000361

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.162G>C (p.K54N) alteration is located in exon 2 (coding exon 2) of the CUX1 gene. This alteration results from a G to C substitution at nucleotide position 162, causing the lysine (K) at amino acid position 54 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;.;.;T;T;.;.;.;D;D;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D;D;.;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.0	.;.;.;.;.;.;.;.;M;M;M;M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D;.;.;D;.;D;D;D;D;D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D;.;.;D;.;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.010	D;.;.;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;.;D;.;D;D;.;.;.
Vest4		0.85
MutPred		0.34		.;.;.;.;.;.;.;.;Loss of methylation at K43 (P = 0.0051);Loss of methylation at K43 (P = 0.0051);Loss of methylation at K43 (P = 0.0051);Loss of methylation at K43 (P = 0.0051);Loss of methylation at K43 (P = 0.0051);
MVP		0.36
MPC		0.65
ClinPred		0.72	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.90

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: rs748511869; hg19: chr7-101559493;