20-57498588-C-T

Variant names:

• chr20-57498588-C-T
• rs28472888
• NM_001386993.1:c.1954G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001386993.1(CTCFL):​c.1954G>A​(p.Val652Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,614,096 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (46 hom.)
• Consequence: CTCFL NM_001386993.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.35
• Publications: 7 publications found

Genes affected

CTCFL (HGNC:16234): (CCCTC-binding factor like) CCCTC-binding factor (CTCF), an 11-zinc-finger factor involved in gene regulation, utilizes different zinc fingers to bind varying DNA target sites. CTCF forms methylation-sensitive insulators that regulate X-chromosome inactivation. This gene is a paralog of CTCF and appears to be expressed primarily in the cytoplasm of spermatocytes, unlike CTCF which is expressed primarily in the nucleus of somatic cells. CTCF and the protein encoded by this gene are normally expressed in a mutually exclusive pattern that correlates with resetting of methylation marks during male germ cell differentiation. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022173226).
• BP6: Variant 20-57498588-C-T is Benign according to our data. Variant chr20-57498588-C-T is described in ClinVar as Benign. ClinVar VariationId is 775652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2159/152286) while in subpopulation AFR AF = 0.0497 (2065/41544). AF 95% confidence interval is 0.0479. There are 61 homozygotes in GnomAd4. There are 1015 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386993.1. 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
	CTCFL	NM_001386993.1	MANE Select	c.1954G>A	p.Val652Met	missense	Exon 11 of 11	NP_001373922.1	Q8NI51-1
	CTCFL	NM_001269043.2		c.1954G>A	p.Val652Met	missense	Exon 11 of 12	NP_001255972.1	Q8NI51-7
	CTCFL	NM_001269040.2		c.1954G>A	p.Val652Met	missense	Exon 11 of 11	NP_001255969.1	Q8NI51-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTCFL	ENST00000243914.8	TSL:1 MANE Select	c.1954G>A	p.Val652Met	missense	Exon 11 of 11	ENSP00000243914.3	Q8NI51-1
	CTCFL	ENST00000423479.7	TSL:1	c.1954G>A	p.Val652Met	missense	Exon 11 of 12	ENSP00000415579.2	Q8NI51-7
	CTCFL	ENST00000371196.6	TSL:1	c.1954G>A	p.Val652Met	missense	Exon 11 of 11	ENSP00000360239.2	Q8NI51-1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2148 AN: 152168 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00356 AC: 894 AN: 251412 AF XY: 0.00269

Gnomad AFR exome AF: 0.0486

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00136 AC: 1981 AN: 1461810 Hom.: 46 Cov.: 32 AF XY: 0.00115 AC XY: 835 AN XY: 727208

African (AFR) AF: 0.0478 AC: 1599 AN: 33476

American (AMR) AF: 0.00271 AC: 121 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5756

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111968

Other (OTH) AF: 0.00315 AC: 190 AN: 60394

GnomAD4 genome AF: 0.0142 AC: 2159 AN: 152286 Hom.: 61 Cov.: 32 AF XY: 0.0136 AC XY: 1015 AN XY: 74464

African (AFR) AF: 0.0497 AC: 2065 AN: 41544

American (AMR) AF: 0.00425 AC: 65 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00495 Hom.: 29

Bravo AF: 0.0160

ESP6500AA AF: 0.0497 AC: 219

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00439 AC: 533

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0020
DANN	Benign	0.89
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PhyloP100		-5.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.036
Sift	Benign	0.15	T
Sift4G	Benign	0.27	T
Polyphen		0.029	B
Vest4		0.093
MVP		0.27
MPC		0.54
ClinPred		0.012	T
GERP RS		-8.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.072
Mutation Taster		=99/1	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: rs28472888; hg19: chr20-56073644;