chr2-219146370-A-C

Variant names:

• chr2-219146370-A-C
• rs2293081
• NM_024782.3:c.588+310T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024782.3(NHEJ1):​c.588+310T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 152,266 control chromosomes in the GnomAD database, including 1,136 homozygotes. 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: 𝑓 0.12 (1136 hom., cov: 32)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0660
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.588+310T>G		intron_variant	Intron 5 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.588+310T>G		intron_variant	Intron 5 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.588+310T>G		intron_variant	Intron 5 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.684+310T>G		intron_variant	Intron 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.588+310T>G		intron_variant	Intron 5 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1710+310T>G		intron_variant	Intron 14 of 16	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18687 AN: 152146 Hom.: 1133 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.0735

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.133

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

GnomAD4 genome AF: 0.123 AC: 18710 AN: 152266 Hom.: 1136 Cov.: 32 AF XY: 0.121 AC XY: 9013 AN XY: 74462

African (AFR) AF: 0.115 AC: 4772 AN: 41550

American (AMR) AF: 0.111 AC: 1694 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 408 AN: 3472

East Asian (EAS) AF: 0.154 AC: 799 AN: 5182

South Asian (SAS) AF: 0.0737 AC: 356 AN: 4828

European-Finnish (FIN) AF: 0.139 AC: 1470 AN: 10604

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.129 AC: 8771 AN: 68024

Other (OTH) AF: 0.135 AC: 284 AN: 2110

Alfa AF: 0.126 Hom.: 2162

Bravo AF: 0.124

Asia WGS AF: 0.141 AC: 488 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.9
DANN	Benign	0.78
PhyloP100		0.066
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2293081; hg19: chr2-220011092;