12-111214214-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_015267.4(CUX2):​c.78C>A​(p.Ser26Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,391,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S26S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CUX2 NM_015267.4 synonymous
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP7: Synonymous conserved (PhyloP=0.439 with no splicing effect.

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1391870 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 691130

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

African (AFR) AF: 0.00 AC: 0 AN: 29610

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 75078

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1078078

Other (OTH) AF: 0.00 AC: 0 AN: 57260

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.4
DANN	Benign	0.72
PhyloP100		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;