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:14
• 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, Orphanet, Ambry Genetics
• severe combined immunodeficiency due to DCLRE1C deficiency

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

ACMG classification

Specifications for DCLRE1C are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033855.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	NM_001033855.3	MANE Select	c.512C>G	p.Pro171Arg	missense	Exon 7 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.512C>G	p.Pro171Arg	missense	Exon 7 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289076.2		c.167C>G	p.Pro56Arg	missense	Exon 5 of 12	NP_001276005.1	Q96SD1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	ENST00000378278.7	TSL:1 MANE Select	c.512C>G	p.Pro171Arg	missense	Exon 7 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.512C>G	p.Pro171Arg	missense	Exon 7 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*170C>G		non_coding_transcript_exon	Exon 5 of 12	ENSP00000350349.3	A0A9S7JGJ5

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	Severe combined immunodeficiency due to DCLRE1C deficiency (5)
-	-	3	not provided (3)
-	-	2	Histiocytic medullary reticulosis (2)
-	-	2	not specified (2)
-	-	1	Severe combined immunodeficiency disease (1)
-	-	1	Severe combined immunodeficiency due to DCLRE1C deficiency;C2700553:Histiocytic medullary reticulosis (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.3	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.023	D
Sift4G	Benign	0.17	T
Polyphen		0.59	P
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;