Genetic Variant ENST00000378289.8:c.1235G>T (chr10-14899234-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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. 14/16 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.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

DCLRE1C
ENST00000378289.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.621

Publications

3 publications found

Variant links:

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 links:

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]

SUV39H2 links:

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ACMG classification

Classification was made for transcript

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUV39H2	NM_001193424.2 link	c.850-305C>A		intron_variant	Intron 3 of 5	ENST00000354919.11	NP_001180353.1	Q9H5I1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUV39H2	ENST00000354919.11 link	c.850-305C>A		intron_variant	Intron 3 of 5	5	NM_001193424.2	ENSP00000346997.6		Q9H5I1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

549896

Hom.:

Cov.:

AF XY:

0.00000336

AC XY:

AN XY:

297708

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15798

American (AMR)

AF:

0.00

AC:

AN:

34702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20012

East Asian (EAS)

AF:

0.00

AC:

AN:

32098

South Asian (SAS)

AF:

0.00

AC:

AN:

62738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3980

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

316810

Other (OTH)

AF:

0.0000327

AC:

AN:

30568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

157

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

6.6

(source)

DANN

Benign

0.86

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.45

M_CAP

Benign

0.0020

MetaRNN

Benign

0.080

MetaSVM

Benign

-1.0

PhyloP100

-0.62

PROVEAN

Benign

0.21

REVEL

Benign

0.072

Sift

Pathogenic

0.0

Sift4G

Benign

0.78

Polyphen

0.029

Vest4

0.13

MutPred

0.57

Gain of ubiquitination at K411 (P = 0.0369);

MVP

0.076

ClinPred

0.12

GERP RS

0.82

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over