rs146712579

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-67637827-C-A
• chr16-67637827-C-G
• chr16-67637827-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_006565.4(CTCF):​c.2139C>A​(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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.22
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 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=0.082888275).
• BP6: Variant 16-67637827-C-A is Benign according to our data. Variant chr16-67637827-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 983075.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTCF	NM_006565.4	c.2139C>A	p.Asn713Lys	missense_variant	Exon 12 of 12	ENST00000264010.10	NP_006556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTCF	ENST00000264010.10	c.2139C>A	p.Asn713Lys	missense_variant	Exon 12 of 12	1	NM_006565.4	ENSP00000264010.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome Uncertain:1 Benign:1

Aug 05, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2024

3billion

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant was identified in at least one patient who was diagnosed with a different variant in another gene and showed no symptoms related to the gene containing the variant in question. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T;.;.;T;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.89	.;.;D;.;.;.;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.083	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.0	L;L;.;.;L;L;.;L
PhyloP100		-2.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.82	N;.;N;.;.;.;.;.
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.
Sift4G	Uncertain	0.014	D;.;D;.;.;.;.;.
Polyphen		0.27	B;B;.;.;B;B;.;B
Vest4		0.28
MutPred		0.15		Gain of ubiquitination at N713 (P = 0.001);Gain of ubiquitination at N713 (P = 0.001);.;.;Gain of ubiquitination at N713 (P = 0.001);Gain of ubiquitination at N713 (P = 0.001);.;Gain of ubiquitination at N713 (P = 0.001);
MVP		0.46
MPC		0.71
ClinPred		0.88	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;