NM_006565.4:c.1208-212T>C

Variant names:

• chr16-67621230-T-C
• rs7191281
• NM_006565.4:c.1208-212T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006565.4(CTCF):​c.1208-212T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 469,084 control chromosomes in the GnomAD database, including 6,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (3292 hom., cov: 32)
  • Exomes 𝑓: 0.12 (2872 hom.)
• Consequence: CTCF NM_006565.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.03
• Publications: 21 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.22).
• BP6: Variant 16-67621230-T-C is Benign according to our data. Variant chr16-67621230-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263720.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTCF	NM_006565.4	c.1208-212T>C		intron_variant	Intron 6 of 11	ENST00000264010.10	NP_006556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTCF	ENST00000264010.10	c.1208-212T>C		intron_variant	Intron 6 of 11	1	NM_006565.4	ENSP00000264010.4

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27304 AN: 151726 Hom.: 3265 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0133

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.165

GnomAD4 exome AF: 0.122 AC: 38614 AN: 317240 Hom.: 2872 Cov.: 4 AF XY: 0.119 AC XY: 19571 AN XY: 163904

African (AFR) AF: 0.339 AC: 3676 AN: 10840

American (AMR) AF: 0.0885 AC: 1295 AN: 14630

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 1116 AN: 10586

East Asian (EAS) AF: 0.0119 AC: 333 AN: 27984

South Asian (SAS) AF: 0.113 AC: 2113 AN: 18724

European-Finnish (FIN) AF: 0.153 AC: 3347 AN: 21866

Middle Eastern (MID) AF: 0.144 AC: 202 AN: 1404

European-Non Finnish (NFE) AF: 0.125 AC: 24077 AN: 191970

Other (OTH) AF: 0.128 AC: 2455 AN: 19236

GnomAD4 genome AF: 0.180 AC: 27383 AN: 151844 Hom.: 3292 Cov.: 32 AF XY: 0.177 AC XY: 13169 AN XY: 74212

African (AFR) AF: 0.334 AC: 13800 AN: 41358

American (AMR) AF: 0.113 AC: 1714 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 359 AN: 3470

East Asian (EAS) AF: 0.0135 AC: 70 AN: 5172

South Asian (SAS) AF: 0.120 AC: 578 AN: 4814

European-Finnish (FIN) AF: 0.164 AC: 1733 AN: 10566

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8600 AN: 67926

Other (OTH) AF: 0.164 AC: 345 AN: 2100

Alfa AF: 0.136 Hom.: 2498

Bravo AF: 0.181

Asia WGS AF: 0.112 AC: 392 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.2
CADD	Benign	0.16
DANN	Benign	0.58
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs7191281; hg19: chr16-67655133;