chr10-14899234-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 13/16 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:4
• 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

Our verdict: Benign. The variant received -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 VariationId 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.

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>T		intron	N/A	NP_001180353.1	Q9H5I1-1
	DCLRE1C	NM_001350965.2		c.*16G>A		3_prime_UTR	Exon 15 of 15	NP_001337894.1	A0A8V8TKN9
	DCLRE1C	NM_001350966.2		c.*16G>A		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>A	p.Arg412Gln	missense	Exon 14 of 14	ENSP00000367538.4	Q96SD1-4
	SUV39H2	ENST00000354919.11	TSL:5 MANE Select	c.850-305C>T		intron	N/A	ENSP00000346997.6	Q9H5I1-1
	SUV39H2	ENST00000313519.9	TSL:1	c.670-305C>T		intron	N/A	ENSP00000319208.5	Q9H5I1-2

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

GnomAD2 exomes AF: 0.111 AC: 14192 AN: 128002 AF XY: 0.119

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 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

African (AFR) AF: 0.108 AC: 1698 AN: 15788

American (AMR) AF: 0.109 AC: 3775 AN: 34678

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 3372 AN: 19994

East Asian (EAS) AF: 0.0703 AC: 2255 AN: 32098

South Asian (SAS) AF: 0.211 AC: 13233 AN: 62628

European-Finnish (FIN) AF: 0.0400 AC: 1329 AN: 33188

Middle Eastern (MID) AF: 0.137 AC: 544 AN: 3978

European-Non Finnish (NFE) AF: 0.0752 AC: 23819 AN: 316718

Other (OTH) AF: 0.0973 AC: 2973 AN: 30548

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

African (AFR) AF: 0.106 AC: 4391 AN: 41434

American (AMR) AF: 0.0974 AC: 1487 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 607 AN: 3468

East Asian (EAS) AF: 0.0511 AC: 264 AN: 5170

South Asian (SAS) AF: 0.208 AC: 1000 AN: 4812

European-Finnish (FIN) AF: 0.0324 AC: 341 AN: 10540

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0734 AC: 4987 AN: 67978

Other (OTH) AF: 0.0940 AC: 198 AN: 2106

Alfa AF: 0.0739 Hom.: 157

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Histiocytic medullary reticulosis (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Severe combined immunodeficiency due to DCLRE1C deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
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
PhyloP100		-0.62
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
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV57955009; COSMIC: COSV57955009;