16-67637827-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006565.4(CTCF):​c.2139C>T​(p.Asn713Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 1,612,658 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (2 hom.)
• Consequence: CTCF NM_006565.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.19).
• BP6: Variant 16-67637827-C-T is Benign according to our data. Variant chr16-67637827-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00063 (96/152328) while in subpopulation AMR AF = 0.00314 (48/15300). AF 95% confidence interval is 0.00243. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 96 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.2139C>T	p.Asn713Asn	synonymous	Exon 12 of 12	NP_006556.1	P49711-1
	CTCF	NM_001438968.1		c.2139C>T	p.Asn713Asn	synonymous	Exon 12 of 12	NP_001425897.1
	CTCF	NM_001363916.2		c.2133C>T	p.Asn711Asn	synonymous	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>T	p.Asn713Asn	synonymous	Exon 12 of 12	ENSP00000264010.4	P49711-1
	CTCF	ENST00000401394.6	TSL:1	c.1155C>T	p.Asn385Asn	synonymous	Exon 10 of 10	ENSP00000384707.1	P49711-2
	CTCF	ENST00000642819.1		c.2139C>T	p.Asn713Asn	synonymous	Exon 11 of 11	ENSP00000494408.1	P49711-1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000470 AC: 118 AN: 251134 AF XY: 0.000427

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000461 AC: 673 AN: 1460330 Hom.: 2 Cov.: 31 AF XY: 0.000454 AC XY: 330 AN XY: 726460

African (AFR) AF: 0.000329 AC: 11 AN: 33434

American (AMR) AF: 0.00170 AC: 76 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00529 AC: 24 AN: 4534

European-Non Finnish (NFE) AF: 0.000439 AC: 488 AN: 1111982

Other (OTH) AF: 0.00105 AC: 63 AN: 60260

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74474

African (AFR) AF: 0.000216 AC: 9 AN: 41574

American (AMR) AF: 0.00314 AC: 48 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68042

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000376 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.2
CADD	Benign	4.0
DANN	Benign	0.76
PhyloP100		-2.2
Mutation Taster		=100/0	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: rs146712579; hg19: chr16-67671730; COSMIC: COSV50470236;