chr10-14934728-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2_SupportingBA1

This summary comes from the ClinGen Evidence Repository: The NM_001033855.3:c.512C>G variant in DCLRE1C is a missense variant predicted to cause the substitution of proline by arginine at amino acid 171 (p.Pro171Arg). This variant has an allele frequency of 0.19422 in the East Asian population in gnomAD, which is above the threshold for BA1 set by the ClinGen SCID VCEP for DCLRE1C (>0.00346). In addition, this variant is present 1394 adult homozygous individuals in gnomADv2.1.1 (distributed in all gnomAD populations)(BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG criteria applied: BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA213684/MONDO:0011225/116

Frequency

Genomes: 𝑓 0.097 ( 785 hom., cov: 31)
Exomes 𝑓: 0.079 ( 5234 hom. )

Consequence

DCLRE1C
NM_001033855.3 missense

Scores

3
8
7

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: 9.66
Variant links:
Genes affected
DCLRE1C (HGNC:17642): (DNA cross-link repair 1C) This gene encodes a nuclear protein that is involved in V(D)J recombination and DNA repair. The encoded protein has single-strand-specific 5'-3' exonuclease activity; it also exhibits endonuclease activity on 5' and 3' overhangs and hairpins. The protein also functions in the regulation of the cell cycle in response to DNA damage. Mutations in this gene can cause Athabascan-type severe combined immunodeficiency (SCIDA) and Omenn syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BS2
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DCLRE1CNM_001033855.3 linkc.512C>G p.Pro171Arg missense_variant Exon 7 of 14 ENST00000378278.7 NP_001029027.1 Q96SD1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DCLRE1CENST00000378278.7 linkc.512C>G p.Pro171Arg missense_variant Exon 7 of 14 1 NM_001033855.3 ENSP00000367527.2 Q96SD1-1

Frequencies

GnomAD3 genomes
AF:
0.0965
AC:
14670
AN:
151980
Hom.:
779
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.130
Gnomad AMI
AF:
0.0614
Gnomad AMR
AF:
0.118
Gnomad ASJ
AF:
0.0804
Gnomad EAS
AF:
0.187
Gnomad SAS
AF:
0.0632
Gnomad FIN
AF:
0.0496
Gnomad MID
AF:
0.0570
Gnomad NFE
AF:
0.0755
Gnomad OTH
AF:
0.0939
GnomAD3 exomes
AF:
0.0903
AC:
22714
AN:
251472
Hom.:
1241
AF XY:
0.0866
AC XY:
11769
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.130
Gnomad AMR exome
AF:
0.121
Gnomad ASJ exome
AF:
0.0777
Gnomad EAS exome
AF:
0.196
Gnomad SAS exome
AF:
0.0638
Gnomad FIN exome
AF:
0.0512
Gnomad NFE exome
AF:
0.0739
Gnomad OTH exome
AF:
0.0886
GnomAD4 exome
AF:
0.0794
AC:
116032
AN:
1460812
Hom.:
5234
Cov.:
33
AF XY:
0.0786
AC XY:
57153
AN XY:
726756
show subpopulations
Gnomad4 AFR exome
AF:
0.131
Gnomad4 AMR exome
AF:
0.122
Gnomad4 ASJ exome
AF:
0.0753
Gnomad4 EAS exome
AF:
0.191
Gnomad4 SAS exome
AF:
0.0652
Gnomad4 FIN exome
AF:
0.0549
Gnomad4 NFE exome
AF:
0.0740
Gnomad4 OTH exome
AF:
0.0867
GnomAD4 genome
AF:
0.0966
AC:
14689
AN:
152098
Hom.:
785
Cov.:
31
AF XY:
0.0958
AC XY:
7127
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.130
Gnomad4 AMR
AF:
0.117
Gnomad4 ASJ
AF:
0.0804
Gnomad4 EAS
AF:
0.186
Gnomad4 SAS
AF:
0.0629
Gnomad4 FIN
AF:
0.0496
Gnomad4 NFE
AF:
0.0755
Gnomad4 OTH
AF:
0.100
Alfa
AF:
0.0747
Hom.:
406
Bravo
AF:
0.104
TwinsUK
AF:
0.0725
AC:
269
ALSPAC
AF:
0.0693
AC:
267
ESP6500AA
AF:
0.128
AC:
564
ESP6500EA
AF:
0.0723
AC:
622
ExAC
AF:
0.0905
AC:
10991
Asia WGS
AF:
0.147
AC:
511
AN:
3478
EpiCase
AF:
0.0734
EpiControl
AF:
0.0754

ClinVar

Significance: Benign
Submissions summary: Benign:13
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to DCLRE1C deficiency Benign:5
May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 26, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 01, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 14, 2023
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

The NM_001033855.3:c.512C>G variant in DCLRE1C is a missense variant predicted to cause the substitution of proline by arginine at amino acid 171 (p.Pro171Arg). This variant has an allele frequency of 0.19422 in the East Asian population in gnomAD, which is above the threshold for BA1 set by the ClinGen SCID VCEP for DCLRE1C (>0.00346). In addition, this variant is present 1394 adult homozygous individuals in gnomADv2.1.1 (distributed in all gnomAD populations)(BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG criteria applied: BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). -

not provided Benign:3
Nov 23, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25917813, 21664875, 23701501, 20674517) -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Histiocytic medullary reticulosis Benign:2
Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 06, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Severe combined immunodeficiency disease Benign:1
Aug 18, 2011
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing;curation

- -

Severe combined immunodeficiency due to DCLRE1C deficiency;C2700553:Histiocytic medullary reticulosis Benign:1
Mar 31, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.093
T
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.59
.;.;.;.;.;.;.;D;.;.;T;T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.83
T;.;.;T;.;.;.;T;T;T;T;T
MetaRNN
Benign
0.0018
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.3
T
MutationAssessor
Uncertain
2.7
M;.;.;.;.;.;.;M;.;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-5.8
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.023
D;T;T;T;T;T;T;T;T;T;D;T
Sift4G
Benign
0.17
T;D;D;D;.;.;.;T;.;.;.;.
Polyphen
0.59
P;D;D;D;.;.;.;B;.;.;.;.
Vest4
0.36
MPC
0.18
ClinPred
0.063
T
GERP RS
4.7
Varity_R
0.67
gMVP
0.84

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35441642; hg19: chr10-14976727; COSMIC: COSV63182512; API