rs35441642

Variant names:

• chr10-14934728-G-C
• rs35441642
• NM_001033855.3:c.512C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-14934728-G-C
• chr10-14934728-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_Supporting BA1

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
• Clinical Significance: Benign reviewed by expert panel B:13
• Conservation: PhyloP100: 9.66
• Publications: 25 publications found

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]

DCLRE1C Gene-Disease associations (from GenCC):

• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet
• severe combined immunodeficiency due to DCLRE1C deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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
DCLRE1C	NM_001033855.3	c.512C>G	p.Pro171Arg	missense_variant	Exon 7 of 14	ENST00000378278.7	NP_001029027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.512C>G	p.Pro171Arg	missense_variant	Exon 7 of 14	1	NM_001033855.3	ENSP00000367527.2

Frequencies

GnomAD3 genomes AF: 0.0965 AC: 14670 AN: 151980 Hom.: 779 Cov.: 31

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

GnomAD2 exomes AF: 0.0903 AC: 22714 AN: 251472 AF XY: 0.0866

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 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

African (AFR) AF: 0.131 AC: 4366 AN: 33434

American (AMR) AF: 0.122 AC: 5462 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0753 AC: 1966 AN: 26116

East Asian (EAS) AF: 0.191 AC: 7585 AN: 39680

South Asian (SAS) AF: 0.0652 AC: 5627 AN: 86238

European-Finnish (FIN) AF: 0.0549 AC: 2934 AN: 53420

Middle Eastern (MID) AF: 0.104 AC: 600 AN: 5764

European-Non Finnish (NFE) AF: 0.0740 AC: 82258 AN: 1111072

Other (OTH) AF: 0.0867 AC: 5234 AN: 60366

GnomAD4 genome AF: 0.0966 AC: 14689 AN: 152098 Hom.: 785 Cov.: 31 AF XY: 0.0958 AC XY: 7127 AN XY: 74376

African (AFR) AF: 0.130 AC: 5404 AN: 41472

American (AMR) AF: 0.117 AC: 1794 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3472

East Asian (EAS) AF: 0.186 AC: 965 AN: 5176

South Asian (SAS) AF: 0.0629 AC: 303 AN: 4820

European-Finnish (FIN) AF: 0.0496 AC: 524 AN: 10574

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0755 AC: 5136 AN: 67998

Other (OTH) AF: 0.100 AC: 211 AN: 2110

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

Submissions by phenotype

Severe combined immunodeficiency due to DCLRE1C deficiency Benign:5

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). -

May 28, 2019

Mendelics

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

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

- -

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.;.;.
PhyloP100		9.7
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
Mutation Taster		=78/22	polymorphism (auto)

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