12-111214217-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_015267.4(CUX2):c.81C>T(p.Val27=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,540,248 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (11 hom.)
• Consequence: CUX2 NM_015267.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0730

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 12-111214217-C-T is Benign according to our data. Variant chr12-111214217-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 713817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.073 with no splicing effect.
• BS2: High AC in GnomAd at 361 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUX2	NM_015267.4	c.81C>T	p.Val27=	synonymous_variant	2/22	ENST00000261726.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUX2	ENST00000261726.11	c.81C>T	p.Val27=	synonymous_variant	2/22	1	NM_015267.4	P1
CUX2	ENST00000397643.3	c.261C>T	p.Val87=	synonymous_variant	3/8	1

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 361 AN: 146586 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000717

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00149

GnomAD3 exomes AF: 0.00206 AC: 428 AN: 207294 Hom.: 0 AF XY: 0.00193 AC XY: 220 AN XY: 113696

Gnomad AFR exome AF: 0.000603

Gnomad AMR exome AF: 0.00100

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00312

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.00192

GnomAD4 exome AF: 0.00300 AC: 4184 AN: 1393588 Hom.: 11 Cov.: 28 AF XY: 0.00298 AC XY: 2061 AN XY: 691728

Gnomad4 AFR exome AF: 0.000739

Gnomad4 AMR exome AF: 0.000879

Gnomad4 ASJ exome AF: 0.000871

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000173

Gnomad4 FIN exome AF: 0.00272

Gnomad4 NFE exome AF: 0.00351

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00246 AC: 361 AN: 146660 Hom.: 1 Cov.: 31 AF XY: 0.00233 AC XY: 166 AN XY: 71112

Gnomad4 AFR AF: 0.000715

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00145

Gnomad4 EAS AF: 0.000199

Gnomad4 SAS AF: 0.000215

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.00387

Gnomad4 OTH AF: 0.00148

Alfa AF: 0.00274 Hom.: 1

Bravo AF: 0.00206

ClinVar

Significance: Benign/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	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CUX2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Developmental and epileptic encephalopathy, 67 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	8.6
Dann	Benign	0.64

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: rs190091435; hg19: chr12-111652021; COSMIC: COSV55639734; COSMIC: COSV55639734;