ERCC6L2

protein-coding

ERCC excision repair 6 like 2

Gene summary

This gene encodes a member of the Snf2 family of helicase-like proteins. The encoded protein may play a role in DNA repair and mitochondrial function. Mutations in this gene have been associated with bone marrow failure syndrome 2. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Apr 2014]

Previous symbols:

C9orf102

MANE transcript

NM_020207.7

Inheritance

ClinVar variants

P:68U:1058B:489

Top phenotype

Bone marrow failure syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr9:95,871,264-96,121,154

External References & Databases

Ensembl (ENSG00000182150)

Transcript & Mutation Effects

hg38 • Region Span ~249.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pancytopenia-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014317

Submitter: PanelApp Australia

pancytopenia-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014317

Submitter: Labcorp Genetics (formerly Invitae)

pancytopenia-developmental delay syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014317

Submitter: G2P

pancytopenia-developmental delay syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014317

Submitter: Ambry Genetics

bone marrow failure syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000159

Submitter: ClinGen

*ERCC6L2* was first reported in relation to autosomal recessive bone marrow failure syndrome in 2014 (Tummala et al., PMID: 24507776). Affected individuals have features of bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. Microcephaly and developmental delay have been described in some individuals. Heterozygote carriers have not been described to have a clinical phenotype. Although *ERCC6L2* is ubiquitously expressed, including across hematopoietic cell lineages, there is a surprising lack of immune phenotype involving T and B-cells in existing literature. Eleven variants (including frameshift, truncating, exon deletion) that have been reported in fourteen probands in nine publications (PMIDs: 24507776, 27185855, 42415356, 41710027, 36952636, 39906419, 37696499, 29633571, 29987015) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence (including in vitro functional assays) (PMIDs: 24507776, 27185855, 32355287, 36156210). Experimental evidence from a study using human A549 cells demonstrates that *ERCC6L2*-knockdown reduced cell survival upon exposure to DNA-damaging agents and also demonstrated that the *ERCC6L2* gene is involved in the DNA-damage response pathway (Tummala et al., PMID: 24507776). In another study, evaluation of patient cells showed DNA repair deficiency due to loss of a DNA repair factor caused by a homozygous nonsense mutation in *ERCC6L2* (Zhang et al., PMID: 27185855). Another experiment found *ERCC6L2*‐deficient cells have decreased colony development of hematopoietic stem progenitor cells and delayed generation of red blood cells, demonstrating a similar phenotype seen in patient cells (Armes et al., PMID: 36156210). In summary, there is definitive evidence supporting the relationship between *ERCC6L2* and autosomal recessive bone marrow failure syndrome. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date August, 20, 2026 (SOP Version 12).

pancytopenia-developmental delay syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014317

Submitter: Orphanet

Clinical Genomic Database (CGD)

Bone marrow failure syndrome 2AR

Manifestation: Hematologic; Neurologic

Intervention: Hematologic

Rationale: Individuals have been described with tri-lineage bone marrow failure, and awareness may allow prompt recognition and management related to hematologic (eg, anemia) and infectious sequelae

Refs: 24507776

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ERCC6L2 variants in ClinVar

13 Conditions Cataloged

Inborn genetic diseasesTotal: 1001

not providedTotal: 981

not specifiedTotal: 86

Pancytopenia-developmental delay syndromeTotal: 58

ERCC6L2-related disorderTotal: 50

ERCC6L2-related disordersTotal: 10

Bone marrow hypocellularityTotal: 3

ThrombocytopeniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020207.7. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	446 clinvar		449
missense		1 clinvar	1044 clinvar	39 clinvar	4 clinvar	1088
nonsense	12 clinvar	6 clinvar				18
start loss						0
frameshift	24 clinvar	16 clinvar	8 clinvar			48
splice donor/acceptor (+/-2bp)	1 clinvar	8 clinvar	3 clinvar			12
Total	37	31	1058	485	4	1615

Highest pathogenic variant AF is 0.0002797196

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 63 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020207.7	RefSeq	NP_064592.3	19	MANE Select
ENST00000653738.2	Ensembl	ENSP00000499221.2	19	MANE Select
NM_001010895.4	RefSeq	NP_001010895.2	14	Standard
NM_001375291.1	RefSeq	NP_001362220.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cellular response to reactive oxygen species
interstrand cross-link repair

Molecular Function

DNA binding
helicase activity
ATP binding
protein kinase binding

Cellular Component

nucleus
cytoplasm
mitochondrion
centrosome
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000288985
Coding exons: 14
Length: 138860
Individuals with no LoFs: 125564
Homozygous LoFs: 1
Heterozygous LoFs: 183
Defined: 125748
p: 0.000732

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.636	334	368	0.907	0.0000182	4661
Missense (PolyPhen)		86	137.19	0.62689		1719
Synonymous	-0.849	141	129	1.10	0.00000634	1344
Loss of Function	3.13	17	37.7	0.450	0.00000215	458

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00040	0.00038	rare
Finnish	0.0053	0.0052	notable
European (Non-Finnish)	0.00046	0.00044	rare
South Asian	0.000098	0.000098	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in early DNA damage response. {ECO:0000269|PubMed:24507776}.;
Disease: DISEASE: Bone marrow failure syndrome 2 (BMFS2) [MIM:615715]: An autosomal recessive disorder characterized by trilineage bone marrow failure, bone marrow hypocellularity, learning difficulties, and microcephaly. Insufficient hematopoiesis results in peripheral blood cytopenias, affecting myeloid, erythroid and megakaryocyte lines. Cutaneous features and increased chromosome breakage are not features. {ECO:0000269|PubMed:24507776}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0840

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	High	Medium	High