20-57524058-C-T

Position:

• chr20-57524058-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001386993.1(CTCFL):​c.148G>A​(p.Glu50Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E50Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CTCFL NM_001386993.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.139

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061818182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTCFL	NM_001386993.1	c.148G>A	p.Glu50Lys	missense_variant	2/11	ENST00000243914.8	NP_001373922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTCFL	ENST00000243914.8	c.148G>A	p.Glu50Lys	missense_variant	2/11	1	NM_001386993.1	ENSP00000243914	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461370 Hom.: 0 Cov.: 66 AF XY: 0.00000138 AC XY: 1 AN XY: 726946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.9
DANN	Benign	0.74
DEOGEN2	Benign	0.051	.;T;T;.;T;T;.;.;.;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.78	T;.;.;T;.;T;T;T;T;T;.;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.062	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;L;L;L;L;L;L;L;L;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.93	N;.;.;N;N;N;.;N;N;.;.;.
REVEL	Benign	0.015
Sift	Benign	0.12	T;.;.;T;T;T;.;T;T;.;.;.
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020	.;B;B;.;B;B;.;.;.;.;.;.
Vest4		0.13
MutPred		0.36		Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);Gain of ubiquitination at E50 (P = 0.0018);
MVP		0.16
MPC		0.039
ClinPred		0.039	T
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.053
gMVP		0.039

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

Publications

LitVar

Other links and lift over

dbSNP: rs6070128; hg19: chr20-56099114; COSMIC: COSV54773056;