rs2052054114

Variant names:

• chr16-67610968-G-A
• rs2052054114
• NM_006565.4:c.136G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-67610968-G-A
• chr16-67610968-G-C

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.136G>A​(p.Asp46Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,482 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CTCF NM_006565.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 8.30
• 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 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=0.26071006).
• BP6: Variant 16-67610968-G-A is Benign according to our data. Variant chr16-67610968-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 975529.Status of the report is no_assertion_criteria_provided, 0 stars.

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.136G>A	p.Asp46Asn	missense	Exon 3 of 12	NP_006556.1	P49711-1
	CTCF	NM_001438968.1		c.136G>A	p.Asp46Asn	missense	Exon 3 of 12	NP_001425897.1
	CTCF	NM_001363916.2		c.136G>A	p.Asp46Asn	missense	Exon 3 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.136G>A	p.Asp46Asn	missense	Exon 3 of 12	ENSP00000264010.4	P49711-1
	CTCF	ENST00000401394.6	TSL:1	c.-32-5777G>A		intron	N/A	ENSP00000384707.1	P49711-2
	CTCF	ENST00000642819.1		c.136G>A	p.Asp46Asn	missense	Exon 2 of 11	ENSP00000494408.1	P49711-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443482 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713940

African (AFR) AF: 0.00 AC: 0 AN: 33128

American (AMR) AF: 0.00 AC: 0 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25682

East Asian (EAS) AF: 0.00 AC: 0 AN: 39164

South Asian (SAS) AF: 0.00 AC: 0 AN: 85462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097542

Other (OTH) AF: 0.00 AC: 0 AN: 59474

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		8.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.24	T
Polyphen		0.18	B
Vest4		0.30
MutPred		0.22		Gain of loop (P = 0.069)
MVP		0.55
MPC		0.49
ClinPred		0.71	D
GERP RS		5.2
PromoterAI		0.00060	Neutral
Varity_R		0.14
gMVP		0.34
Mutation Taster		=53/47	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: rs2052054114; hg19: chr16-67644871; COSMIC: COSV50461814; COSMIC: COSV50461814;