2-219095357-T-C

Variant names:

• chr2-219095357-T-C
• rs10498064
• NM_024782.3:c.589-17151A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024782.3(NHEJ1):​c.589-17151A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000628 in 318,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: NHEJ1 NM_024782.3 intron
• Scores: Splicing: ADA: 0.00003395
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339
• Publications: 0 publications found

Genes affected

NHEJ1 (HGNC:25737): (non-homologous end joining factor 1) Double-strand breaks in DNA result from genotoxic stresses and are among the most damaging of DNA lesions. This gene encodes a DNA repair factor essential for the nonhomologous end-joining pathway, which preferentially mediates repair of double-stranded breaks. Mutations in this gene cause different kinds of severe combined immunodeficiency disorders. [provided by RefSeq, Jul 2008]

NHEJ1 Gene-Disease associations (from GenCC):

• Cernunnos-XLF deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000280537 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024782.3. 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
	NHEJ1	NM_024782.3	MANE Select	c.589-17151A>G		intron	N/A	NP_079058.1	Q9H9Q4-1
	NHEJ1	NM_001377499.1		c.589-17151A>G		intron	N/A	NP_001364428.1	H7C0G7
	NHEJ1	NM_001377498.1		c.589-17151A>G		intron	N/A	NP_001364427.1	Q9H9Q4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	ENST00000356853.10	TSL:1 MANE Select	c.589-17151A>G		intron	N/A	ENSP00000349313.5	Q9H9Q4-1
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1711-17151A>G		intron	N/A	ENSP00000320919.3	F8W735
	NHEJ1	ENST00000881108.1		c.589-5369A>G		intron	N/A	ENSP00000551167.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000628 AC: 2 AN: 318552 Hom.: 0 Cov.: 0 AF XY: 0.00000556 AC XY: 1 AN XY: 180000

African (AFR) AF: 0.00 AC: 0 AN: 8612

American (AMR) AF: 0.00 AC: 0 AN: 27264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10782

East Asian (EAS) AF: 0.00 AC: 0 AN: 9210

South Asian (SAS) AF: 0.00 AC: 0 AN: 59700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2778

European-Non Finnish (NFE) AF: 0.0000126 AC: 2 AN: 158850

Other (OTH) AF: 0.00 AC: 0 AN: 14304

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.9
DANN	Benign	0.58
PhyloP100		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.15		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: rs10498064; hg19: chr2-219960079;