rs766699328

Positions:

• chr10-14934472-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.586C>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Arginine by Tryptophan at amino acid 196 (p.Arg196Trp).The filtering allele frequency (the upper threshold of the 95% CI of 4/59978 alleles) of the c.586C>T variant in DCLRE1C is 0.00002256 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5416774/MONDO:0011225/116

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCLRE1C	NM_001033855.3	c.586C>T	p.Arg196Trp	missense_variant	8/14	ENST00000378278.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.586C>T	p.Arg196Trp	missense_variant	8/14	1	NM_001033855.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251458 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461894 Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74288

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Athabaskan severe combined immunodeficiency Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 12, 2020

- -

Severe combined immunodeficiency due to DCLRE1C deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 07, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 196 of the DCLRE1C protein (p.Arg196Trp). This variant is present in population databases (rs766699328, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 576525). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Pathogenic	1.0
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;.;.;D;.;.;.;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.34	N;.;.;.;.;.;.;N;.;.;.
MutationTaster	Benign	0.89	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;.;.;.;D;.;.;.
Polyphen		0.99	D;D;D;D;.;.;.;D;.;.;.
Vest4		0.39
MutPred		0.52		Loss of helix (P = 0.0626);.;.;.;.;.;.;Loss of helix (P = 0.0626);.;.;.;
MVP		0.95
MPC		0.16
ClinPred		0.76	D
GERP RS		3.3
Varity_R		0.38
gMVP		0.56

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

Other links and lift over

dbSNP: rs766699328; hg19: chr10-14976471; COSMIC: COSV105912811; COSMIC: COSV105912811;