rs6436114

Variant names:

• chr2-219138112-T-G
• rs6436114
• NM_024782.3:c.588+8568A>C

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+8568A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 151,980 control chromosomes in the GnomAD database, including 39,978 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 0.72 (39978 hom., cov: 31)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.588
• Publications: 11 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.588+8568A>C		intron_variant	Intron 5 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.588+8568A>C		intron_variant	Intron 5 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.588+8568A>C		intron_variant	Intron 5 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.684+8568A>C		intron_variant	Intron 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.588+8568A>C		intron_variant	Intron 5 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1710+8568A>C		intron_variant	Intron 14 of 16	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109563 AN: 151862 Hom.: 39960 Cov.: 31

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.695

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

GnomAD4 genome AF: 0.721 AC: 109630 AN: 151980 Hom.: 39978 Cov.: 31 AF XY: 0.719 AC XY: 53375 AN XY: 74272

African (AFR) AF: 0.706 AC: 29212 AN: 41400

American (AMR) AF: 0.641 AC: 9777 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 2434 AN: 3472

East Asian (EAS) AF: 0.453 AC: 2339 AN: 5166

South Asian (SAS) AF: 0.622 AC: 2996 AN: 4820

European-Finnish (FIN) AF: 0.820 AC: 8666 AN: 10572

Middle Eastern (MID) AF: 0.623 AC: 182 AN: 292

European-Non Finnish (NFE) AF: 0.765 AC: 51978 AN: 67988

Other (OTH) AF: 0.689 AC: 1452 AN: 2108

Alfa AF: 0.740 Hom.: 22173

Bravo AF: 0.706

Asia WGS AF: 0.496 AC: 1726 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		-0.59
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: rs6436114; hg19: chr2-220002834;