GeneBe

X-72205594-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017669.4(ERCC6L):​c.3173A>C​(p.Gln1058Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,403 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

ERCC6L
NM_017669.4 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.36

Publications

0 publications found
Variant links:
Genes affected
ERCC6L (HGNC:20794): (ERCC excision repair 6 like, spindle assembly checkpoint helicase) This gene encodes a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF2) family of proteins, and contains a SNF2-like ATPase domain and a PICH family domain. One distinguishing feature of this SWI/SNF protein family member is that during interphase, the protein is excluded from the nucleus, and only associates with chromatin after the nuclear envelope has broken down. This protein is a DNA translocase that is thought to bind double-stranded DNA that is exposed to stretching forces, such as those exerted by the mitotic spindle. This protein associates with ribosomal DNA and ultra-fine DNA bridges (UFBs), fine structures that connect sister chromatids during anaphase at some sites such as fragile sites, telomeres and centromeres. This gene is required for the faithful segregation of sister chromatids during mitosis, and the ATPase activity of this protein required for the resolution of UFBs before cytokinesis. [provided by RefSeq, May 2017]
PIN4 (HGNC:8992): (peptidylprolyl cis/trans isomerase, NIMA-interacting 4) This gene encodes a member of the parvulin subfamily of the peptidyl-prolyl cis/trans isomerase protein family. The encoded protein catalyzes the isomerization of peptidylprolyl bonds, and may play a role in the cell cycle, chromatin remodeling, and/or ribosome biogenesis. The encoded protein may play an additional role in the mitochondria. [provided by RefSeq, Dec 2009]

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12205872).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERCC6LNM_017669.4 linkc.3173A>C p.Gln1058Pro missense_variant Exon 2 of 2 ENST00000334463.4 NP_060139.2 Q2NKX8
ERCC6LNM_001009954.3 linkc.2804A>C p.Gln935Pro missense_variant Exon 3 of 3 NP_001009954.1
PIN4NM_001170747.1 linkc.312+8690T>G intron_variant Intron 3 of 3 NP_001164218.1 Q9Y237-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERCC6LENST00000334463.4 linkc.3173A>C p.Gln1058Pro missense_variant Exon 2 of 2 1 NM_017669.4 ENSP00000334675.3 Q2NKX8

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1097403
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
362805
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26388
American (AMR)
AF:
0.00
AC:
0
AN:
35175
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19376
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30187
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54029
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40505
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4136
European-Non Finnish (NFE)
AF:
0.00000119
AC:
1
AN:
841544
Other (OTH)
AF:
0.00
AC:
0
AN:
46063
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
24
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 26, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3173A>C (p.Q1058P) alteration is located in exon 2 (coding exon 2) of the ERCC6L gene. This alteration results from a A to C substitution at nucleotide position 3173, causing the glutamine (Q) at amino acid position 1058 to be replaced by a proline (P). 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
0.070
BayesDel_addAF
Uncertain
0.014
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
14
DANN
Benign
0.97
DEOGEN2
Benign
0.052
T;T
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.66
T;T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.30
T
MutationAssessor
Uncertain
2.3
.;M
PhyloP100
1.4
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.19
Sift
Benign
0.070
T;T
Sift4G
Benign
0.21
T;T
Polyphen
0.21
.;B
Vest4
0.22
MutPred
0.19
.;Loss of stability (P = 0.0646);
MVP
0.80
MPC
0.73
ClinPred
0.21
T
GERP RS
4.3
Varity_R
0.29
gMVP
0.24
Mutation Taster
=95/5
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

Publications

Other links and lift over

hg19: chrX-71425444; API