12-111214217-C-T

Variant names:

• chr12-111214217-C-T
• rs190091435
• NM_015267.4:c.81C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001370598.1(CUX2):​c.-106C>T variant causes a 5 prime UTR premature start codon gain 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_001370598.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0730
• Publications: 1 publications found

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]

CUX2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 67

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 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 Benign/Likely_benign. ClinVar VariationId is 713817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 361 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370598.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX2	NM_015267.4	MANE Select	c.81C>T	p.Val27Val	synonymous	Exon 2 of 22	NP_056082.2	O14529
	CUX2	NM_001370598.1		c.-106C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	NP_001357527.1
	CUX2	NM_001370598.1		c.-106C>T		5_prime_UTR	Exon 2 of 22	NP_001357527.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX2	ENST00000261726.11	TSL:1 MANE Select	c.81C>T	p.Val27Val	synonymous	Exon 2 of 22	ENSP00000261726.6	O14529
	CUX2	ENST00000397643.3	TSL:1	c.261C>T	p.Val87Val	synonymous	Exon 3 of 8	ENSP00000380765.3	F5GWR6
	CUX2	ENST00000933089.1		c.81C>T	p.Val27Val	synonymous	Exon 2 of 21	ENSP00000603148.1

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

GnomAD2 exomes AF: 0.00206 AC: 428 AN: 207294 AF XY: 0.00193

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 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

African (AFR) AF: 0.000739 AC: 22 AN: 29750

American (AMR) AF: 0.000879 AC: 29 AN: 33008

Ashkenazi Jewish (ASJ) AF: 0.000871 AC: 21 AN: 24104

East Asian (EAS) AF: 0.00 AC: 0 AN: 37134

South Asian (SAS) AF: 0.000173 AC: 13 AN: 75052

European-Finnish (FIN) AF: 0.00272 AC: 142 AN: 52296

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5496

European-Non Finnish (NFE) AF: 0.00351 AC: 3788 AN: 1079418

Other (OTH) AF: 0.00293 AC: 168 AN: 57330

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

African (AFR) AF: 0.000715 AC: 28 AN: 39178

American (AMR) AF: 0.00177 AC: 26 AN: 14668

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3456

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5026

South Asian (SAS) AF: 0.000215 AC: 1 AN: 4658

European-Finnish (FIN) AF: 0.00396 AC: 36 AN: 9098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00387 AC: 261 AN: 67368

Other (OTH) AF: 0.00148 AC: 3 AN: 2022

Alfa AF: 0.00274 Hom.: 1

Bravo AF: 0.00206

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 67 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.6
DANN	Benign	0.64
PhyloP100		0.073
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

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