rs35441642

Positions:

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

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]

DCLRE1C links:

Genome browser will be placed here

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/exons	MANE	Protein	UniProt
DCLRE1C	NM_001033855.3 linkuse as main transcript	c.512C>G	p.Pro171Arg	missense_variant	7/14	ENST00000378278.7	NP_001029027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7 linkuse as main transcript	c.512C>G	p.Pro171Arg	missense_variant	7/14	1	NM_001033855.3	ENSP00000367527	P2	Q96SD1-1

Frequencies

GnomAD3 genomes

AF:

0.0965

AC:

14670

AN:

151980

Hom.:

779

Cov.:

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.:

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.:

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

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	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). -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25917813, 21664875, 23701501, 20674517) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Histiocytic medullary reticulosis

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Severe combined immunodeficiency disease

Benign:1

Benign, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Severe combined immunodeficiency due to DCLRE1C deficiency;C2700553:Histiocytic medullary reticulosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

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

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

MutationAssessor

Uncertain

2.7

M;.;.;.;.;.;.;M;.;.;.;.

MutationTaster

Benign

2.7e-8

P;P;P;P;P;P;P;P;P;P

PrimateAI

Uncertain

0.67

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over