rs41296438

Variant names:

• chr10-14945124-C-G
• rs41296438
• NM_001033855.3:c.227G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-14945124-C-G
• chr10-14945124-C-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.227G>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Arginine by Threonine at amino acid 76 p.Arg76Thr.The filtering allele frequency (the lower threshold of the 95% CI of 713/24912) of the c.227G>C variant in DCLRE1C is 0.02613 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00346) for BA1, and therefore meets this criterion (BA1). Additionally, there have been descriptions of 11 homozygous individuals.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: BA1. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5416971/MONDO:0011225/116

• Frequency:
  • Genomes: 𝑓 0.0078 (21 hom., cov: 30)
  • Exomes 𝑓: 0.00078 (15 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.123
• Publications: 2 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 -8 ACMG points.

• 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.227G>C	p.Arg76Thr	missense	Exon 3 of 14	NP_001029027.1	Q96SD1-1
	DCLRE1C	NM_001350965.2		c.227G>C	p.Arg76Thr	missense	Exon 3 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001289078.2		c.-63G>C		5_prime_UTR	Exon 2 of 12	NP_001276007.1	Q96SD1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	ENST00000378278.7	TSL:1 MANE Select	c.227G>C	p.Arg76Thr	missense	Exon 3 of 14	ENSP00000367527.2	Q96SD1-1
	DCLRE1C	ENST00000378289.8	TSL:1	c.227G>C	p.Arg76Thr	missense	Exon 3 of 14	ENSP00000367538.4	Q96SD1-4
	DCLRE1C	ENST00000378246.6	TSL:1	n.227G>C		non_coding_transcript_exon	Exon 3 of 13	ENSP00000367492.3	A0A8V8TKP5

Frequencies

GnomAD3 genomes AF: 0.00778 AC: 1183 AN: 152048 Hom.: 21 Cov.: 30

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00192 AC: 482 AN: 251112 AF XY: 0.00139

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000781 AC: 1140 AN: 1460164 Hom.: 15 Cov.: 30 AF XY: 0.000679 AC XY: 493 AN XY: 726298

African (AFR) AF: 0.0297 AC: 993 AN: 33420

American (AMR) AF: 0.000560 AC: 25 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5694

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111266

Other (OTH) AF: 0.00167 AC: 101 AN: 60306

GnomAD4 genome AF: 0.00779 AC: 1186 AN: 152166 Hom.: 21 Cov.: 30 AF XY: 0.00754 AC XY: 561 AN XY: 74390

African (AFR) AF: 0.0273 AC: 1134 AN: 41512

American (AMR) AF: 0.00229 AC: 35 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68002

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.000735 Hom.: 1

Bravo AF: 0.00908

ESP6500AA AF: 0.0281 AC: 124

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00235 AC: 285

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	0.089
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.84	L
PhyloP100		0.12
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.10
Sift	Benign	0.39	T
Sift4G	Benign	0.33	T
Polyphen		0.0020	B
Vest4		0.41
MVP		0.63
MPC		0.081
ClinPred		0.0033	T
GERP RS		2.3
Varity_R		0.28
gMVP		0.53
Mutation Taster		=98/2	polymorphism

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: rs41296438; hg19: chr10-14987123;