rs1224246553

Variant names:

• chr7-101816042-T-C
• rs1224246553
• NM_001913.5:c.12T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001913.5(CUX1):​c.12T>C​(p.Asn4Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000705 in 1,417,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: CUX1 NM_001913.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.10
• Publications: 1 publications found

Genes affected

CUX1 (HGNC:2557): (cut like homeobox 1) The protein encoded by this gene is a member of the homeodomain family of DNA binding proteins. It may regulate gene expression, morphogenesis, and differentiation and it may also play a role in the cell cycle progession. Several alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Feb 2011]

CUX1 Gene-Disease associations (from GenCC):

• global developmental delay with or without impaired intellectual development

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  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=-0.5).
• BP6: Variant 7-101816042-T-C is Benign according to our data. Variant chr7-101816042-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 752193.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000708 (9/1271592) while in subpopulation AMR AF = 0.000201 (7/34912). AF 95% confidence interval is 0.000094. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001913.5. 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
	CUX1	NM_001913.5	MANE Plus Clinical	c.12T>C	p.Asn4Asn	synonymous	Exon 1 of 23	NP_001904.2
	CUX1	NM_001202543.2		c.12T>C	p.Asn4Asn	synonymous	Exon 1 of 24	NP_001189472.1	P39880-3
	CUX1	NM_181500.4		c.12T>C	p.Asn4Asn	synonymous	Exon 1 of 23	NP_852477.1	Q13948-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX1	ENST00000622516.6	TSL:1 MANE Plus Clinical	c.12T>C	p.Asn4Asn	synonymous	Exon 1 of 23	ENSP00000484760.2	Q13948-1
	CUX1	ENST00000360264.7	TSL:1	c.12T>C	p.Asn4Asn	synonymous	Exon 1 of 24	ENSP00000353401.3	P39880-3
	CUX1	ENST00000292538.9	TSL:1	c.12T>C	p.Asn4Asn	synonymous	Exon 1 of 23	ENSP00000292538.4	Q13948-1

Frequencies

GnomAD3 genomes AF: 0.00000685 AC: 1 AN: 145976 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000676

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000141 AC: 3 AN: 212470 AF XY: 0.00000860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000102

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: 0.00

GnomAD4 exome AF: 0.00000708 AC: 9 AN: 1271592 Hom.: 0 Cov.: 30 AF XY: 0.00000632 AC XY: 4 AN XY: 632964

African (AFR) AF: 0.00 AC: 0 AN: 24874

American (AMR) AF: 0.000201 AC: 7 AN: 34912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19010

East Asian (EAS) AF: 0.00 AC: 0 AN: 22886

South Asian (SAS) AF: 0.00 AC: 0 AN: 79758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4820

European-Non Finnish (NFE) AF: 0.00000201 AC: 2 AN: 994130

Other (OTH) AF: 0.00 AC: 0 AN: 47948

GnomAD4 genome AF: 0.00000685 AC: 1 AN: 145976 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 71126

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

African (AFR) AF: 0.00 AC: 0 AN: 40530

American (AMR) AF: 0.0000676 AC: 1 AN: 14794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3380

East Asian (EAS) AF: 0.00 AC: 0 AN: 4784

South Asian (SAS) AF: 0.00 AC: 0 AN: 4664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65896

Other (OTH) AF: 0.00 AC: 0 AN: 2038

⚠️ 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: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions as Germline

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	-0.50
CADD	Benign	19
DANN	Benign	0.40
PhyloP100		4.1
PromoterAI		0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1224246553; hg19: chr7-101459322;