2-219076557-C-CTTTTTT

Variant names:

• chr2-219076557-C-CTTTTTT
• rs778354452
• NM_024782.3:c.826-108_826-103dupAAAAAA

Variant summary

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

The NM_024782.3(NHEJ1):​c.826-108_826-103dupAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000298 in 335,198 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: not found (cov: 28)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000280537 (HGNC:):

ACMG classification

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.826-108_826-103dupAAAAAA		intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.841-108_841-103dupAAAAAA		intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.826-108_826-103dupAAAAAA		intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.1004-108_1004-103dupAAAAAA		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.826-103_826-102insAAAAAA		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1948-103_*1948-102insAAAAAA		intron_variant	Intron 16 of 16	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000298 AC: 1 AN: 335198 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 184004

⚠️ 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: 43216

European-Finnish (FIN) AF: 0.0000592 AC: 1 AN: 16880

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 204188

Other (OTH) AF: 0.00 AC: 0 AN: 17436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;