rs12768894

Positions:

chr10-14932906-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.728A>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Histidine by Arginine at amino acid 243 (p.His243Arg).The filtering allele frequency (the lower threshold of the 95% CI of 13221/60002) of the c.728A>G variant in DCLRE1C is 0.2249 for Admixed American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00346) for BA1, and therefore meets this criterion (BA1). Additionally, 23214 adult homozygous have been reported (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5416704/MONDO:0011225/116

Frequency

Genomes: 𝑓 0.15 ( 1801 hom., cov: 32)

Exomes 𝑓: 0.17 ( 21413 hom. )

Consequence

DCLRE1C
NM_001033855.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.25

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

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCLRE1C	NM_001033855.3 linkuse as main transcript	c.728A>G	p.His243Arg	missense_variant	9/14	ENST00000378278.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCLRE1C	ENST00000378278.7 linkuse as main transcript	c.728A>G	p.His243Arg	missense_variant	9/14	1	NM_001033855.3	P2	Q96SD1-1

Frequencies

GnomAD3 genomes

AF:

0.148

AC:

22472

AN:

152102

Hom.:

1801

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0962

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.0967

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.165

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.173

Gnomad OTH

AF:

0.147

GnomAD3 exomes

AF:

0.159

AC:

39917

AN:

251460

Hom.:

3383

AF XY:

0.156

AC XY:

21190

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0918

Gnomad AMR exome

AF:

0.229

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.109

Gnomad SAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.154

Gnomad NFE exome

AF:

0.169

Gnomad OTH exome

AF:

0.152

GnomAD4 exome

AF:

0.169

AC:

246450

AN:

1461064

Hom.:

21413

Cov.:

AF XY:

0.167

AC XY:

121215

AN XY:

726874

show subpopulations

Gnomad4 AFR exome

AF:

0.0951

Gnomad4 AMR exome

AF:

0.229

Gnomad4 ASJ exome

AF:

0.117

Gnomad4 EAS exome

AF:

0.0984

Gnomad4 SAS exome

AF:

0.128

Gnomad4 FIN exome

AF:

0.154

Gnomad4 NFE exome

AF:

0.176

Gnomad4 OTH exome

AF:

0.163

GnomAD4 genome

AF:

0.148

AC:

22484

AN:

152220

Hom.:

1801

Cov.:

AF XY:

0.149

AC XY:

11067

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0963

Gnomad4 AMR

AF:

0.196

Gnomad4 ASJ

AF:

0.118

Gnomad4 EAS

AF:

0.0963

Gnomad4 SAS

AF:

0.122

Gnomad4 FIN

AF:

0.165

Gnomad4 NFE

AF:

0.173

Gnomad4 OTH

AF:

0.147

Alfa

AF:

0.159

Hom.:

1826

Bravo

AF:

0.150

TwinsUK

AF:

0.171

AC:

635

ALSPAC

AF:

0.173

AC:

665

ESP6500AA

AF:

0.0983

AC:

433

ESP6500EA

AF:

0.165

AC:

1422

ExAC

AF:

0.156

AC:

18944

Asia WGS

AF:

0.102

AC:

353

AN:

3478

EpiCase

AF:

0.169

EpiControl

AF:

0.168

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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	Jan 13, 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. -

Severe combined immunodeficiency due to DCLRE1C deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.097

.;.;.;.;.;.;.;T;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.73

T;.;.;T;.;.;.;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.;.;.;.;.;.;L;.;.

MutationTaster

Benign

0.99

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

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.7

N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.058

Sift

Benign

0.28

T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.60

T;T;T;T;.;.;.;T;.;.

Polyphen

0.0050

B;P;P;P;.;.;.;B;.;.

Vest4

0.13

MPC

0.050

ClinPred

0.0086

GERP RS

4.2

Varity_R

0.23

gMVP

0.44

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