2-219077265-GC-AA

Position:

• chr2-219077265-GC-AA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024782.3(NHEJ1):​c.805_806delinsTT​(p.Ala269Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A269V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NHEJ1 NM_024782.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHEJ1	NM_024782.3	c.805_806delinsTT	p.Ala269Leu	missense_variant	7/8	ENST00000356853.10
NHEJ1	NM_001377498.1	c.805_806delinsTT	p.Ala269Leu	missense_variant	7/8
NHEJ1	NM_001377499.1	c.820_821delinsTT	p.Ala274Leu	missense_variant	7/8
NHEJ1	NR_165304.1	n.983_984delinsTT		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHEJ1	ENST00000356853.10	c.805_806delinsTT	p.Ala269Leu	missense_variant	7/8	1	NM_024782.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cernunnos-XLF deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2023	This sequence change replaces alanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 269 of the NHEJ1 protein (p.Ala269Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NHEJ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1380965). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 21, 2021	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-219941987;