NM_015267.4:c.78C>T

Variant names:

• chr12-111214214-C-T
• rs778761089
• NM_015267.4:c.78C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_015267.4(CUX2):​c.78C>T​(p.Ser26Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000565 in 1,539,458 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000046 (1 hom.)
• Consequence: CUX2 NM_015267.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.439
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 12-111214214-C-T is Benign according to our data. Variant chr12-111214214-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1694674.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.439 with no splicing effect.
• BS2: High AC in GnomAd4 at 23 AD gene.

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.78C>T	p.Ser26Ser	synonymous	Exon 2 of 22	NP_056082.2	O14529
	CUX2	NM_001370598.1		c.-109C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	NP_001357527.1
	CUX2	NM_001370598.1		c.-109C>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.78C>T	p.Ser26Ser	synonymous	Exon 2 of 22	ENSP00000261726.6	O14529
	CUX2	ENST00000397643.3	TSL:1	c.258C>T	p.Ser86Ser	synonymous	Exon 3 of 8	ENSP00000380765.3	F5GWR6
	CUX2	ENST00000933089.1		c.78C>T	p.Ser26Ser	synonymous	Exon 2 of 21	ENSP00000603148.1

Frequencies

GnomAD3 genomes AF: 0.000156 AC: 23 AN: 147502 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000675

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000859

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000493

GnomAD2 exomes AF: 0.000126 AC: 26 AN: 206790 AF XY: 0.000123

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000423

GnomAD4 exome AF: 0.0000460 AC: 64 AN: 1391866 Hom.: 1 Cov.: 27 AF XY: 0.0000593 AC XY: 41 AN XY: 691128

African (AFR) AF: 0.000169 AC: 5 AN: 29608

American (AMR) AF: 0.000152 AC: 5 AN: 32898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24108

East Asian (EAS) AF: 0.00 AC: 0 AN: 37056

South Asian (SAS) AF: 0.000626 AC: 47 AN: 75078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52298

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5484

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078076

Other (OTH) AF: 0.0000524 AC: 3 AN: 57260

GnomAD4 genome AF: 0.000156 AC: 23 AN: 147592 Hom.: 0 Cov.: 31 AF XY: 0.000112 AC XY: 8 AN XY: 71748

African (AFR) AF: 0.000431 AC: 17 AN: 39460

American (AMR) AF: 0.0000674 AC: 1 AN: 14828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.000861 AC: 4 AN: 4644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67468

Other (OTH) AF: 0.000488 AC: 1 AN: 2048

Alfa AF: 0.000106 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CUX2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.75
PhyloP100		0.44
Mutation Taster		=99/1	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: rs778761089; hg19: chr12-111652018; COSMIC: COSV55635817; COSMIC: COSV55635817;