chr20-57498588-C-T

Position:

• chr20-57498588-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 61 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTCFL	NM_001386993.1	c.1954G>A	p.Val652Met	missense_variant	11/11	ENST00000243914.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTCFL	ENST00000243914.8	c.1954G>A	p.Val652Met	missense_variant	11/11	1	NM_001386993.1	P4

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

GnomAD3 exomes AF: 0.00356 AC: 894 AN: 251412 Hom.: 21 AF XY: 0.00269 AC XY: 366 AN XY: 135878

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 SAS exome AF: 0.0000654

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

Gnomad4 AFR exome AF: 0.0478

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.00315

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

Gnomad4 AFR AF: 0.0497

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00234 Hom.: 14

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

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;T;.;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.52	T;.;.;T;.;T
MetaRNN	Benign	0.0022	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;N;N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.15	N;.;.;N;N;N
REVEL	Benign	0.036
Sift	Benign	0.15	T;.;.;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T;T
Polyphen		0.029	.;B;B;.;B;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

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: rs28472888; hg19: chr20-56073644;