ENST00000378289.8:c.1235G>T

Variant names:

• chr10-14899234-C-A
• rs60006238
• ENST00000378289.8:c.1235G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000378289.8(DCLRE1C):​c.1235G>T​(p.Arg412Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 549,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R412Q) has been classified as Benign. The gene DCLRE1C is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: DCLRE1C ENST00000378289.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.621
• Publications: 3 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]

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

Specifications for DCLRE1C are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07959086).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000378289.8. 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
	SUV39H2	NM_001193424.2	MANE Select	c.850-305C>A		intron	N/A	NP_001180353.1	Q9H5I1-1
	DCLRE1C	NM_001350965.2		c.*16G>T		3_prime_UTR	Exon 15 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001350966.2		c.*16G>T		3_prime_UTR	Exon 13 of 13	NP_001337895.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	ENST00000378289.8	TSL:1	c.1235G>T	p.Arg412Leu	missense	Exon 14 of 14	ENSP00000367538.4	Q96SD1-4
	SUV39H2	ENST00000354919.11	TSL:5 MANE Select	c.850-305C>A		intron	N/A	ENSP00000346997.6	Q9H5I1-1
	SUV39H2	ENST00000313519.9	TSL:1	c.670-305C>A		intron	N/A	ENSP00000319208.5	Q9H5I1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000182 AC: 1 AN: 549896 Hom.: 0 Cov.: 0 AF XY: 0.00000336 AC XY: 1 AN XY: 297708

African (AFR) AF: 0.00 AC: 0 AN: 15798

American (AMR) AF: 0.00 AC: 0 AN: 34702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20012

East Asian (EAS) AF: 0.00 AC: 0 AN: 32098

South Asian (SAS) AF: 0.00 AC: 0 AN: 62738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3980

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 316810

Other (OTH) AF: 0.0000327 AC: 1 AN: 30568

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 157

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.6
DANN	Benign	0.86
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.62
PROVEAN	Benign	0.21	N
REVEL	Benign	0.072
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.78	T
Polyphen		0.029	B
Vest4		0.13
MutPred		0.57		Gain of ubiquitination at K411 (P = 0.0369)
MVP		0.076
ClinPred		0.12	T
GERP RS		0.82
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: rs60006238; hg19: chr10-14941233;