X-126165116-A-C

Variant names:

• chrX-126165116-A-C
• rs200667384
• NM_001013628.3:c.809T>G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001013628.3(DCAF12L2):​c.809T>G​(p.Phe270Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000397 in 1,210,663 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 174 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., 12 hem., cov: 26)
  • Exomes 𝑓: 0.00040 (0 hom. 162 hem.)
• Consequence: DCAF12L2 NM_001013628.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.24

Genes affected

DCAF12L2 (HGNC:32950): (DDB1 and CUL4 associated factor 12 like 2) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by Gly-His and Trp-Asp (GH-WD), which may facilitate formation of heterotrimeric or multi-protein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene appears to represent an intronless retrocopy of a related multi-exon gene located on chromosome 9. However, the CDS of this intronless gene remains intact, it is conserved in other mammalian species, it is known to be transcribed, and it is therefore thought to encode a functional protein. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09553155).
• BP6: Variant X-126165116-A-C is Benign according to our data. Variant chrX-126165116-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2661381.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chrX-126165116-A-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCAF12L2	NM_001013628.3	c.809T>G	p.Phe270Cys	missense_variant	Exon 1 of 1	ENST00000360028.4	NP_001013650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCAF12L2	ENST00000360028.4	c.809T>G	p.Phe270Cys	missense_variant	Exon 1 of 1	6	NM_001013628.3	ENSP00000353128.2

Frequencies

GnomAD3 genomes AF: 0.000398 AC: 45 AN: 112938 Hom.: 0 Cov.: 26 AF XY: 0.000342 AC XY: 12 AN XY: 35084

Gnomad AFR AF: 0.0000643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000554

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000525

Gnomad OTH AF: 0.000654

GnomAD3 exomes AF: 0.000485 AC: 88 AN: 181573 Hom.: 0 AF XY: 0.000391 AC XY: 26 AN XY: 66479

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000531

Gnomad FIN exome AF: 0.00151

Gnomad NFE exome AF: 0.000741

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000397 AC: 436 AN: 1097725 Hom.: 0 Cov.: 36 AF XY: 0.000446 AC XY: 162 AN XY: 363111

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.000435

Gnomad4 OTH exome AF: 0.000347

GnomAD4 genome AF: 0.000398 AC: 45 AN: 112938 Hom.: 0 Cov.: 26 AF XY: 0.000342 AC XY: 12 AN XY: 35084

Gnomad4 AFR AF: 0.0000643

Gnomad4 AMR AF: 0.000554

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00127

Gnomad4 NFE AF: 0.000525

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.0000707 Hom.: 2

Bravo AF: 0.000389

ExAC AF: 0.000511 AC: 62

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.809T>G (p.F270C) alteration is located in exon 1 (coding exon 1) of the DCAF12L2 gene. This alteration results from a T to G substitution at nucleotide position 809, causing the phenylalanine (F) at amino acid position 270 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DCAF12L2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.47
Sift	Benign	0.055	T
Sift4G	Uncertain	0.051	T
Polyphen		0.090	B
Vest4		0.52
MVP		0.71
ClinPred		0.10	T
GERP RS		3.4
Varity_R		0.34
gMVP		0.94

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: rs200667384; hg19: chrX-125299099;