NM_006565.4:c.2139C>G

Variant names:

• chr16-67637827-C-G
• rs146712579
• NM_006565.4:c.2139C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006565.4(CTCF):​c.2139C>G​(p.Asn713Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N713N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTCF NM_006565.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.22
• Publications: 0 publications found

Genes affected

CTCF (HGNC:13723): (CCCTC-binding factor) This gene is a member of the BORIS + CTCF gene family and encodes a transcriptional regulator protein with 11 highly conserved zinc finger (ZF) domains. This nuclear protein is able to use different combinations of the ZF domains to bind different DNA target sequences and proteins. Depending upon the context of the site, the protein can bind a histone acetyltransferase (HAT)-containing complex and function as a transcriptional activator or bind a histone deacetylase (HDAC)-containing complex and function as a transcriptional repressor. If the protein is bound to a transcriptional insulator element, it can block communication between enhancers and upstream promoters, thereby regulating imprinted expression. Mutations in this gene have been associated with invasive breast cancers, prostate cancers, and Wilms' tumors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

CTCF Gene-Disease associations (from GenCC):

• intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CTCF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.4399 (above the threshold of 3.09). Trascript score misZ: 4.8366 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome, syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.084124565).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006565.4. 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
	CTCF	NM_006565.4	MANE Select	c.2139C>G	p.Asn713Lys	missense	Exon 12 of 12	NP_006556.1	P49711-1
	CTCF	NM_001438968.1		c.2139C>G	p.Asn713Lys	missense	Exon 12 of 12	NP_001425897.1
	CTCF	NM_001363916.2		c.2133C>G	p.Asn711Lys	missense	Exon 12 of 12	NP_001350845.1	A0A2R8YFL0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTCF	ENST00000264010.10	TSL:1 MANE Select	c.2139C>G	p.Asn713Lys	missense	Exon 12 of 12	ENSP00000264010.4	P49711-1
	CTCF	ENST00000401394.6	TSL:1	c.1155C>G	p.Asn385Lys	missense	Exon 10 of 10	ENSP00000384707.1	P49711-2
	CTCF	ENST00000642819.1		c.2139C>G	p.Asn713Lys	missense	Exon 11 of 11	ENSP00000494408.1	P49711-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.0	L
PhyloP100		-2.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.27	B
Vest4		0.28
MutPred		0.15		Gain of ubiquitination at N713 (P = 0.001)
MVP		0.46
MPC		0.71
ClinPred		0.78	D
GERP RS		-7.1
Varity_R		0.43
gMVP		0.67
Mutation Taster		=18/82	disease causing

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: rs146712579; hg19: chr16-67671730;