2-219158192-TC-CT

Variant names:

• chr2-219158192-TC-CT
• NM_024782.3:c.170_171delGAinsAG
• NHEJ1 p.Arg57Gln

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM5

The NM_024782.3(NHEJ1):​c.170_171delGAinsAG​(p.Arg57Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R57G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NHEJ1 NM_024782.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46
• 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, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000280537 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-219158194-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 981.

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.170_171delGAinsAG	p.Arg57Gln	missense	N/A	NP_079058.1	Q9H9Q4-1
	NHEJ1	NM_001377499.1		c.170_171delGAinsAG	p.Arg57Gln	missense	N/A	NP_001364428.1	H7C0G7
	NHEJ1	NM_001377498.1		c.170_171delGAinsAG	p.Arg57Gln	missense	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.170_171delGAinsAG	p.Arg57Gln	missense	N/A	ENSP00000349313.5	Q9H9Q4-1
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1292_*1293delGAinsAG		non_coding_transcript_exon	Exon 11 of 17	ENSP00000320919.3	F8W735
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1292_*1293delGAinsAG		3_prime_UTR	Exon 11 of 17	ENSP00000320919.3	F8W735

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-220022914;