chr16-67610850-C-T

Variant names:

• chr16-67610850-C-T
• rs549711902
• NM_006565.4:c.18C>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.18C>T​(p.Val6Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000636 in 1,485,572 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (17 hom.)
• Consequence: CTCF NM_006565.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.117
• Publications: 1 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=-1.03).
• BP6: Variant 16-67610850-C-T is Benign according to our data. Variant chr16-67610850-C-T is described in ClinVar as Benign. ClinVar VariationId is 745878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.117 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00046 (70/152172) while in subpopulation SAS AF = 0.0141 (68/4818). AF 95% confidence interval is 0.0114. There are 1 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 70 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.18C>T	p.Val6Val	synonymous	Exon 3 of 12	NP_006556.1	P49711-1
	CTCF	NM_001438968.1		c.18C>T	p.Val6Val	synonymous	Exon 3 of 12	NP_001425897.1
	CTCF	NM_001363916.2		c.18C>T	p.Val6Val	synonymous	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.18C>T	p.Val6Val	synonymous	Exon 3 of 12	ENSP00000264010.4	P49711-1
	CTCF	ENST00000401394.6	TSL:1	c.-32-5895C>T		intron	N/A	ENSP00000384707.1	P49711-2
	CTCF	ENST00000642819.1		c.18C>T	p.Val6Val	synonymous	Exon 2 of 11	ENSP00000494408.1	P49711-1

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152054 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00122 AC: 214 AN: 175906 AF XY: 0.00145

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000347

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.000656 AC: 875 AN: 1333400 Hom.: 17 Cov.: 31 AF XY: 0.000925 AC XY: 600 AN XY: 648978

African (AFR) AF: 0.0000334 AC: 1 AN: 29926

American (AMR) AF: 0.00 AC: 0 AN: 27910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19358

East Asian (EAS) AF: 0.00 AC: 0 AN: 38388

South Asian (SAS) AF: 0.0127 AC: 772 AN: 60950

European-Finnish (FIN) AF: 0.0000409 AC: 2 AN: 48912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5200

European-Non Finnish (NFE) AF: 0.0000515 AC: 54 AN: 1047904

Other (OTH) AF: 0.000839 AC: 46 AN: 54852

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152172 Hom.: 1 Cov.: 32 AF XY: 0.000659 AC XY: 49 AN XY: 74398

African (AFR) AF: 0.0000241 AC: 1 AN: 41516

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000249 Hom.: 0

Bravo AF: 0.000110

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	7.7
DANN	Benign	0.83
PhyloP100		-0.12
PromoterAI		0.0018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs549711902; hg19: chr16-67644753;