chrX-126164741-G-A

Variant names:

• chrX-126164741-G-A
• rs2147243799
• NM_001013628.3:c.1184C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001013628.3(DCAF12L2):​c.1184C>T​(p.Pro395Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,098,169 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.000012 (0 hom. 3 hem.)
• Consequence: DCAF12L2 NM_001013628.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.324
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.112941265).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCAF12L2	NM_001013628.3	c.1184C>T	p.Pro395Leu	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.1184C>T	p.Pro395Leu	missense_variant	Exon 1 of 1	6	NM_001013628.3	ENSP00000353128.2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.0000118 AC: 13 AN: 1098169 Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 3 AN XY: 363525

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000154 AC: 13 AN: 842072

Other (OTH) AF: 0.00 AC: 0 AN: 46095

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1184C>T (p.P395L) alteration is located in exon 1 (coding exon 1) of the DCAF12L2 gene. This alteration results from a C to T substitution at nucleotide position 1184, causing the proline (P) at amino acid position 395 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.7
DANN	Benign	0.64
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.89	L
PhyloP100		0.32
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.022
Sift	Benign	0.18	T
Sift4G	Benign	0.39	T
Polyphen		0.010	B
Vest4		0.079
MutPred		0.24		Loss of disorder (P = 0.0402);
MVP		0.29
ClinPred		0.078	T
GERP RS		0.25
Varity_R		0.065
gMVP		0.71
Mutation Taster		=94/6	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: rs2147243799; hg19: chrX-125298724; COSMIC: COSV100758744;