10-14899206-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000378289.8(DCLRE1C):c.1263C>G(p.Ser421Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 702,086 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (8 hom.)
• Consequence: DCLRE1C ENST00000378289.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.885

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077061355).
• BP6: Variant 10-14899206-G-C is Benign according to our data. Variant chr10-14899206-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2570766.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00296 (451/152206) while in subpopulation NFE AF= 0.00537 (365/68000). AF 95% confidence interval is 0.00491. There are 2 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUV39H2	NM_001193424.2	c.850-333G>C		intron_variant		ENST00000354919.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUV39H2	ENST00000354919.11	c.850-333G>C		intron_variant		5	NM_001193424.2	P1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152088 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00254 AC: 325 AN: 128082 Hom.: 2 AF XY: 0.00254 AC XY: 178 AN XY: 70134

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.000247

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000447

Gnomad FIN exome AF: 0.00316

Gnomad NFE exome AF: 0.00479

Gnomad OTH exome AF: 0.00351

GnomAD4 exome AF: 0.00333 AC: 1833 AN: 549880 Hom.: 8 Cov.: 0 AF XY: 0.00317 AC XY: 944 AN XY: 297694

Gnomad4 AFR exome AF: 0.00101

Gnomad4 AMR exome AF: 0.00245

Gnomad4 ASJ exome AF: 0.000150

Gnomad4 EAS exome AF: 0.0000312

Gnomad4 SAS exome AF: 0.000478

Gnomad4 FIN exome AF: 0.00238

Gnomad4 NFE exome AF: 0.00478

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152206 Hom.: 2 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74422

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00537

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00373 Hom.: 1

Bravo AF: 0.00292

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00415 AC: 16

ExAC AF: 0.000634 AC: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

DCLRE1C: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.0
Dann	Benign	0.58
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.086
Sift	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.66		Gain of MoRF binding (P = 0.0054);
MVP		0.12
ClinPred		0.025	T
GERP RS		-0.59

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: rs76797003; hg19: chr10-14941205;