2-219076505-G-A

Variant names:

• chr2-219076505-G-A
• rs114490958
• NM_024782.3:c.826-50C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024782.3(NHEJ1):​c.826-50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,460,644 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (86 hom., cov: 30)
  • Exomes 𝑓: 0.0019 (80 hom.)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0520
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-219076505-G-A is Benign according to our data. Variant chr2-219076505-G-A is described in ClinVar as [Benign]. Clinvar id is 1294277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.826-50C>T		intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.841-50C>T		intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.826-50C>T		intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.1004-50C>T		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.826-50C>T		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1948-50C>T		intron_variant	Intron 16 of 16	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2568 AN: 150414 Hom.: 85 Cov.: 30

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.0112

GnomAD2 exomes AF: 0.00440 AC: 1031 AN: 234400 AF XY: 0.00315

Gnomad AFR exome AF: 0.0604

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000579

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000184

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00187 AC: 2451 AN: 1310164 Hom.: 80 Cov.: 22 AF XY: 0.00158 AC XY: 1035 AN XY: 654934

African (AFR) AF: 0.0635 AC: 1925 AN: 30304

American (AMR) AF: 0.00348 AC: 144 AN: 41326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23286

East Asian (EAS) AF: 0.00 AC: 0 AN: 33906

South Asian (SAS) AF: 0.000290 AC: 24 AN: 82750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47186

Middle Eastern (MID) AF: 0.00185 AC: 9 AN: 4866

European-Non Finnish (NFE) AF: 0.000104 AC: 103 AN: 993038

Other (OTH) AF: 0.00460 AC: 246 AN: 53502

GnomAD4 genome AF: 0.0171 AC: 2572 AN: 150480 Hom.: 86 Cov.: 30 AF XY: 0.0166 AC XY: 1216 AN XY: 73406

African (AFR) AF: 0.0593 AC: 2434 AN: 41016

American (AMR) AF: 0.00641 AC: 97 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5064

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000251 AC: 17 AN: 67630

Other (OTH) AF: 0.0111 AC: 23 AN: 2080

Alfa AF: 0.00664 Hom.: 7

Bravo AF: 0.0197

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.59
PhyloP100		0.052
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: rs114490958; hg19: chr2-219941227;