chr10-14926856-G-C

Variant names:

• chr10-14926856-G-C
• rs41298896
• NM_001033855.3:c.959C>G

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.959C>G variant in DCLRE1C is a missense variant predicted to cause substitution of serine by cysteine at amino acid 320 (p.Ser320Cys). This variant has an allele frequency of 0.03553 in the African / African American population in gnomAD, which is above the threshold for BA1 set by the ClinGen SCID VCEP for DCLRE1C (>0.00346). In addition, 16 adult homozygous individuals with this variant are present in gnomAD v2.1.1 (in African/African American population)(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/CA290573/MONDO:0011225/116

• Frequency:
  • Genomes: 𝑓 0.010 (23 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (20 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:8
• Conservation: PhyloP100: 8.99
• Publications: 9 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

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.959C>G	p.Ser320Cys	missense	Exon 11 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.959C>G	p.Ser320Cys	missense	Exon 11 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289076.2		c.614C>G	p.Ser205Cys	missense	Exon 9 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.959C>G	p.Ser320Cys	missense	Exon 11 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.959C>G	p.Ser320Cys	missense	Exon 11 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*617C>G		non_coding_transcript_exon	Exon 9 of 12	ENSP00000350349.3	A0A9S7JGJ5

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1583 AN: 152114 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00577

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00275 AC: 691 AN: 251342 AF XY: 0.00200

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00110 AC: 1607 AN: 1460850 Hom.: 20 Cov.: 30 AF XY: 0.000959 AC XY: 697 AN XY: 726808

African (AFR) AF: 0.0370 AC: 1236 AN: 33444

American (AMR) AF: 0.00239 AC: 107 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5762

European-Non Finnish (NFE) AF: 0.0000675 AC: 75 AN: 1111150

Other (OTH) AF: 0.00252 AC: 152 AN: 60342

GnomAD4 genome AF: 0.0104 AC: 1583 AN: 152234 Hom.: 23 Cov.: 31 AF XY: 0.00958 AC XY: 713 AN XY: 74422

African (AFR) AF: 0.0352 AC: 1463 AN: 41540

American (AMR) AF: 0.00576 AC: 88 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00180 Hom.: 5

Bravo AF: 0.0121

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0370 AC: 163

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	4	not provided (5)
-	-	2	Severe combined immunodeficiency due to DCLRE1C deficiency (2)
-	-	1	Athabaskan severe combined immunodeficiency (1)
-	-	1	Histiocytic medullary reticulosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.91	P
Vest4		0.96
MVP		0.87
MPC		0.30
ClinPred		0.057	T
GERP RS		5.0
Varity_R		0.67
gMVP		0.87
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41298896; hg19: chr10-14968855;