10-14899234-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000378289.8(DCLRE1C):c.1235G>A(p.Arg412Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0946 in 701,600 control chromosomes in the GnomAD database, including 4,107 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (677 hom., cov: 32)
  • Exomes 𝑓: 0.096 (3430 hom.)
• Consequence: DCLRE1C ENST00000378289.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.621

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]

SUV39H2 (HGNC:17287): (SUV39H2 histone lysine methyltransferase) Enables S-adenosyl-L-methionine binding activity; histone methyltransferase activity (H3-K9 specific); and zinc ion binding activity. Involved in chromatin assembly or disassembly and chromatin remodeling. Acts upstream of or within cellular response to hypoxia and negative regulation of transcription by RNA polymerase II. Located in chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060653985).
• BP6: Variant 10-14899234-C-T is Benign according to our data. Variant chr10-14899234-C-T is described in ClinVar as [Benign]. Clinvar id is 1255460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUV39H2	NM_001193424.2	c.850-305C>T		intron_variant		ENST00000354919.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUV39H2	ENST00000354919.11	c.850-305C>T		intron_variant		5	NM_001193424.2	P1

Frequencies

GnomAD3 genomes AF: 0.0880 AC: 13360 AN: 151864 Hom.: 677 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0968

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.0509

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.0950

GnomAD3 exomes AF: 0.111 AC: 14192 AN: 128002 Hom.: 1073 AF XY: 0.119 AC XY: 8347 AN XY: 70094

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0388

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.0418

Gnomad NFE exome AF: 0.0771

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.0964 AC: 52998 AN: 549618 Hom.: 3430 Cov.: 0 AF XY: 0.104 AC XY: 30814 AN XY: 297546

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.0703

Gnomad4 SAS exome AF: 0.211

Gnomad4 FIN exome AF: 0.0400

Gnomad4 NFE exome AF: 0.0752

Gnomad4 OTH exome AF: 0.0973

GnomAD4 genome AF: 0.0881 AC: 13385 AN: 151982 Hom.: 677 Cov.: 32 AF XY: 0.0892 AC XY: 6630 AN XY: 74292

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0974

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.0511

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.0324

Gnomad4 NFE AF: 0.0734

Gnomad4 OTH AF: 0.0940

Alfa AF: 0.0685 Hom.: 116

Bravo AF: 0.0916

TwinsUK AF: 0.0720 AC: 267

ALSPAC AF: 0.0724 AC: 279

ExAC AF: 0.114 AC: 2236

Asia WGS AF: 0.113 AC: 391 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -

Histiocytic medullary reticulosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Severe combined immunodeficiency due to DCLRE1C deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	8.9
Dann	Benign	0.84
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.078
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.45	T
Polyphen		0.67	P
Vest4		0.036
ClinPred		0.015	T
GERP RS		0.82

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: rs60006238; hg19: chr10-14941233; COSMIC: COSV57955009; COSMIC: COSV57955009;