NM_015267.4:c.64-10A>T

Variant names:

• chr12-111214190-A-T
• rs201254067
• NM_015267.4:c.64-10A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_015267.4(CUX2):​c.64-10A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (0 hom., cov: 21)
  • Exomes 𝑓: 0.024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CUX2 NM_015267.4 intron
• Scores: Splicing: ADA: 0.0009105
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.82
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-111214190-A-T is Benign according to our data. Variant chr12-111214190-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 771184.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015267.4. 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.64-10A>T		intron	N/A	NP_056082.2	O14529
	CUX2	NM_001370598.1		c.-123-10A>T		intron	N/A	NP_001357527.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX2	ENST00000261726.11	TSL:1 MANE Select	c.64-10A>T		intron	N/A	ENSP00000261726.6	O14529
	CUX2	ENST00000397643.3	TSL:1	c.244-10A>T		intron	N/A	ENSP00000380765.3	F5GWR6
	CUX2	ENST00000933089.1		c.64-10A>T		intron	N/A	ENSP00000603148.1

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 1862 AN: 68662 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.00940

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0166

Gnomad EAS AF: 0.0178

Gnomad SAS AF: 0.0320

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.0170

Gnomad NFE AF: 0.0220

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.308 AC: 16195 AN: 52566 AF XY: 0.309

Gnomad AFR exome AF: 0.370

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.368

Gnomad FIN exome AF: 0.408

Gnomad NFE exome AF: 0.247

Gnomad OTH exome AF: 0.277

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0243 AC: 18853 AN: 774860 Hom.: 0 Cov.: 16 AF XY: 0.0286 AC XY: 10842 AN XY: 379244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0308 AC: 441 AN: 14318

American (AMR) AF: 0.131 AC: 1508 AN: 11544

Ashkenazi Jewish (ASJ) AF: 0.0370 AC: 469 AN: 12660

East Asian (EAS) AF: 0.0422 AC: 931 AN: 22084

South Asian (SAS) AF: 0.144 AC: 3679 AN: 25550

European-Finnish (FIN) AF: 0.120 AC: 3513 AN: 29260

Middle Eastern (MID) AF: 0.0659 AC: 183 AN: 2778

European-Non Finnish (NFE) AF: 0.0121 AC: 7531 AN: 624676

Other (OTH) AF: 0.0187 AC: 598 AN: 31990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0272 AC: 1866 AN: 68652 Hom.: 0 Cov.: 21 AF XY: 0.0257 AC XY: 876 AN XY: 34108

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0456 AC: 721 AN: 15804

American (AMR) AF: 0.0149 AC: 110 AN: 7378

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 30 AN: 1812

East Asian (EAS) AF: 0.0175 AC: 42 AN: 2400

South Asian (SAS) AF: 0.0319 AC: 69 AN: 2162

European-Finnish (FIN) AF: 0.0303 AC: 141 AN: 4654

Middle Eastern (MID) AF: 0.0187 AC: 3 AN: 160

European-Non Finnish (NFE) AF: 0.0220 AC: 721 AN: 32802

Other (OTH) AF: 0.0253 AC: 24 AN: 948

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.86
PhyloP100		1.8
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00091
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.10		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: rs201254067; hg19: chr12-111651994; COSMIC: COSV55649920;