rs145727304

Variant names:

• chr16-67636779-C-T
• rs145727304
• NM_006565.4:c.1927C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-67636779-C-T
• chr16-67636779-C-A
• chr16-67636779-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006565.4(CTCF):​c.1927C>T​(p.Pro643Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00468 in 1,605,712 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (20 hom.)
• Consequence: CTCF NM_006565.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 6.11
• Publications: 14 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: Benign. The variant received -19 ACMG points.

• 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=0.008668512).
• BP6: Variant 16-67636779-C-T is Benign according to our data. Variant chr16-67636779-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00294 (447/152080) while in subpopulation NFE AF = 0.0054 (367/67990). AF 95% confidence interval is 0.00494. There are 2 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 447 AD gene.

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.1927C>T	p.Pro643Ser	missense	Exon 11 of 12	NP_006556.1	P49711-1
	CTCF	NM_001438968.1		c.1927C>T	p.Pro643Ser	missense	Exon 11 of 12	NP_001425897.1
	CTCF	NM_001363916.2		c.1927C>T	p.Pro643Ser	missense	Exon 11 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.1927C>T	p.Pro643Ser	missense	Exon 11 of 12	ENSP00000264010.4	P49711-1
	CTCF	ENST00000401394.6	TSL:1	c.943C>T	p.Pro315Ser	missense	Exon 9 of 10	ENSP00000384707.1	P49711-2
	CTCF	ENST00000642819.1		c.1927C>T	p.Pro643Ser	missense	Exon 10 of 11	ENSP00000494408.1	P49711-1

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 151964 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00540

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00231 AC: 567 AN: 245598 AF XY: 0.00236

Gnomad AFR exome AF: 0.000880

Gnomad AMR exome AF: 0.000705

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.00255

GnomAD4 exome AF: 0.00487 AC: 7074 AN: 1453632 Hom.: 20 Cov.: 31 AF XY: 0.00470 AC XY: 3400 AN XY: 722810

African (AFR) AF: 0.000602 AC: 20 AN: 33208

American (AMR) AF: 0.000732 AC: 32 AN: 43696

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39104

South Asian (SAS) AF: 0.0000474 AC: 4 AN: 84352

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00608 AC: 6740 AN: 1108046

Other (OTH) AF: 0.00423 AC: 254 AN: 60086

GnomAD4 genome AF: 0.00294 AC: 447 AN: 152080 Hom.: 2 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74322

African (AFR) AF: 0.00123 AC: 51 AN: 41472

American (AMR) AF: 0.00144 AC: 22 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00540 AC: 367 AN: 67990

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00444 Hom.: 6

Bravo AF: 0.00295

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00213 AC: 258

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	not specified (2)
-	-	1	CTCF-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.20
Sift	Benign	0.067	T
Sift4G	Benign	0.082	T
Polyphen		0.99	D
Vest4		0.46
MVP		0.37
MPC		1.6
ClinPred		0.034	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.46
Mutation Taster		=32/68	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: rs145727304; hg19: chr16-67670682; COSMIC: COSV50470912;