2-219076557-C-CT

Variant names:

• chr2-219076557-C-CT
• rs778354452
• NM_024782.3:c.826-103dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_024782.3(NHEJ1):​c.826-103dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0512 in 445,678 control chromosomes in the GnomAD database, including 88 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (87 hom., cov: 28)
  • Exomes 𝑓: 0.059 (1 hom.)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-219076557-C-CT is Benign according to our data. Variant chr2-219076557-C-CT is described in ClinVar as [Benign]. Clinvar id is 1234916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.826-103dupA		intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.841-103dupA		intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.826-103dupA		intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.1004-103dupA		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_826-102insA		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1948-103_*1948-102insA		intron_variant	Intron 16 of 16	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 3788 AN: 122378 Hom.: 87 Cov.: 28

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.0443

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.00905

Gnomad SAS AF: 0.0115

Gnomad FIN AF: 0.00441

Gnomad MID AF: 0.0119

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0267

GnomAD4 exome AF: 0.0588 AC: 19016 AN: 323324 Hom.: 1 AF XY: 0.0585 AC XY: 10365 AN XY: 177308

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

African (AFR) AF: 0.0739 AC: 640 AN: 8660

American (AMR) AF: 0.0626 AC: 923 AN: 14736

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 521 AN: 9454

East Asian (EAS) AF: 0.0530 AC: 928 AN: 17500

South Asian (SAS) AF: 0.0747 AC: 3046 AN: 40750

European-Finnish (FIN) AF: 0.0489 AC: 805 AN: 16456

Middle Eastern (MID) AF: 0.0620 AC: 78 AN: 1258

European-Non Finnish (NFE) AF: 0.0563 AC: 11123 AN: 197602

Other (OTH) AF: 0.0563 AC: 952 AN: 16908

⚠️ 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 AF: 0.0310 AC: 3790 AN: 122354 Hom.: 87 Cov.: 28 AF XY: 0.0303 AC XY: 1777 AN XY: 58578

African (AFR) AF: 0.0627 AC: 2041 AN: 32552

American (AMR) AF: 0.0179 AC: 211 AN: 11808

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 76 AN: 2970

East Asian (EAS) AF: 0.00909 AC: 40 AN: 4400

South Asian (SAS) AF: 0.0116 AC: 45 AN: 3882

European-Finnish (FIN) AF: 0.00441 AC: 27 AN: 6124

Middle Eastern (MID) AF: 0.0130 AC: 3 AN: 230

European-Non Finnish (NFE) AF: 0.0219 AC: 1268 AN: 57940

Other (OTH) AF: 0.0265 AC: 44 AN: 1658

Alfa AF: 0.0164 Hom.: 57

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism

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: rs778354452; hg19: chr2-219941279;