rs12768894

Variant names:

• chr10-14932906-T-C
• rs12768894
• NM_001033855.3:c.728A>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 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
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 2.25
• Publications: 30 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.728A>G	p.His243Arg	missense	Exon 9 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.728A>G	p.His243Arg	missense	Exon 9 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289076.2		c.383A>G	p.His128Arg	missense	Exon 7 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.728A>G	p.His243Arg	missense	Exon 9 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.728A>G	p.His243Arg	missense	Exon 9 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*386A>G		non_coding_transcript_exon	Exon 7 of 12	ENSP00000350349.3	A0A9S7JGJ5

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22472 AN: 152102 Hom.: 1801 Cov.: 32

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

GnomAD2 exomes AF: 0.159 AC: 39917 AN: 251460 AF XY: 0.156

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 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.: 34 AF XY: 0.167 AC XY: 121215 AN XY: 726874

African (AFR) AF: 0.0951 AC: 3182 AN: 33470

American (AMR) AF: 0.229 AC: 10223 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3045 AN: 26132

East Asian (EAS) AF: 0.0984 AC: 3906 AN: 39698

South Asian (SAS) AF: 0.128 AC: 11066 AN: 86238

European-Finnish (FIN) AF: 0.154 AC: 8238 AN: 53418

Middle Eastern (MID) AF: 0.192 AC: 1105 AN: 5766

European-Non Finnish (NFE) AF: 0.176 AC: 195874 AN: 1111256

Other (OTH) AF: 0.163 AC: 9811 AN: 60364

GnomAD4 genome AF: 0.148 AC: 22484 AN: 152220 Hom.: 1801 Cov.: 32 AF XY: 0.149 AC XY: 11067 AN XY: 74408

African (AFR) AF: 0.0963 AC: 3999 AN: 41546

American (AMR) AF: 0.196 AC: 2998 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 410 AN: 3470

East Asian (EAS) AF: 0.0963 AC: 499 AN: 5180

South Asian (SAS) AF: 0.122 AC: 589 AN: 4826

European-Finnish (FIN) AF: 0.165 AC: 1752 AN: 10588

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11735 AN: 68010

Other (OTH) AF: 0.147 AC: 310 AN: 2114

Alfa AF: 0.157 Hom.: 5038

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Severe combined immunodeficiency due to DCLRE1C deficiency (3)
-	-	2	Histiocytic medullary reticulosis (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.058
Sift	Benign	0.28	T
Sift4G	Benign	0.60	T
Polyphen		0.0050	B
Vest4		0.13
MPC		0.050
ClinPred		0.0086	T
GERP RS		4.2
Varity_R		0.23
gMVP		0.44
Mutation Taster		=98/2	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: rs12768894; hg19: chr10-14974905; COSMIC: COSV63183127; COSMIC: COSV63183127;