2-219076557-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTT

Variant names:

• chr2-219076557-C-CTTTTT
• rs778354452
• NM_024782.3:c.826-107_826-103dupAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024782.3(NHEJ1):​c.826-107_826-103dupAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000597 in 335,174 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000082 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000060 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.188
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ENSG00000280537 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

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.826-107_826-103dupAAAAA		intron	N/A	NP_079058.1	Q9H9Q4-1
	NHEJ1	NM_001377499.1		c.841-107_841-103dupAAAAA		intron	N/A	NP_001364428.1	H7C0G7
	NHEJ1	NM_001377498.1		c.826-107_826-103dupAAAAA		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.826-103_826-102insAAAAA		intron	N/A	ENSP00000349313.5	Q9H9Q4-1
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1948-103_*1948-102insAAAAA		intron	N/A	ENSP00000320919.3	F8W735
	NHEJ1	ENST00000881108.1		c.892-103_892-102insAAAAA		intron	N/A	ENSP00000551167.1

Frequencies

GnomAD3 genomes AF: 0.00000816 AC: 1 AN: 122534 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000172

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000597 AC: 2 AN: 335174 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 183988

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 8954

American (AMR) AF: 0.00 AC: 0 AN: 15420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9718

East Asian (EAS) AF: 0.00 AC: 0 AN: 18096

South Asian (SAS) AF: 0.00 AC: 0 AN: 43208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1290

European-Non Finnish (NFE) AF: 0.00000490 AC: 1 AN: 204176

Other (OTH) AF: 0.0000574 AC: 1 AN: 17436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000816 AC: 1 AN: 122534 Hom.: 0 Cov.: 28 AF XY: 0.0000171 AC XY: 1 AN XY: 58630

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32604

American (AMR) AF: 0.00 AC: 0 AN: 11814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2976

East Asian (EAS) AF: 0.00 AC: 0 AN: 4418

South Asian (SAS) AF: 0.00 AC: 0 AN: 3900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.0000172 AC: 1 AN: 57998

Other (OTH) AF: 0.00 AC: 0 AN: 1654

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000692 Hom.: 57

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19

Splicing

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

Other links and lift over

dbSNP: rs778354452; hg19: chr2-219941279;