2-219076224-G-A

Variant names:

• chr2-219076224-G-A
• rs79018048
• ENST00000318673.6:n.*2179C>T

Variant summary

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

The ENST00000318673.6(ENSG00000280537):​n.*2179C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,508,130 control chromosomes in the GnomAD database, including 191 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 0.019 (106 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (85 hom.)
• Consequence: ENSG00000280537 ENST00000318673.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.769
• Publications: 0 publications found

Genes affected

ENSG00000280537 (HGNC:):

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.*157C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000356853.10	NP_079058.1
NHEJ1	NR_165304.1	n.1235C>T		non_coding_transcript_exon_variant	Exon 9 of 9
NHEJ1	NM_001377499.1	c.*157C>T		3_prime_UTR_variant	Exon 8 of 8		NP_001364428.1
NHEJ1	NM_001377498.1	c.*157C>T		3_prime_UTR_variant	Exon 8 of 8		NP_001364427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000280537	ENST00000318673.6	n.*2179C>T		non_coding_transcript_exon_variant	Exon 17 of 17	2		ENSP00000320919.3
NHEJ1	ENST00000356853.10	c.*157C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*2179C>T		3_prime_UTR_variant	Exon 17 of 17	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2898 AN: 152182 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.0659

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00196 AC: 2659 AN: 1355830 Hom.: 85 Cov.: 25 AF XY: 0.00170 AC XY: 1137 AN XY: 668516

African (AFR) AF: 0.0681 AC: 2087 AN: 30628

American (AMR) AF: 0.00405 AC: 138 AN: 34036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23726

East Asian (EAS) AF: 0.00 AC: 0 AN: 35654

South Asian (SAS) AF: 0.000315 AC: 24 AN: 76300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42676

Middle Eastern (MID) AF: 0.00125 AC: 5 AN: 3996

European-Non Finnish (NFE) AF: 0.000103 AC: 108 AN: 1052408

Other (OTH) AF: 0.00527 AC: 297 AN: 56406

GnomAD4 genome AF: 0.0191 AC: 2907 AN: 152300 Hom.: 106 Cov.: 32 AF XY: 0.0185 AC XY: 1381 AN XY: 74478

African (AFR) AF: 0.0659 AC: 2738 AN: 41538

American (AMR) AF: 0.00817 AC: 125 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68022

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00728 Hom.: 9

Bravo AF: 0.0222

Asia WGS AF: 0.00433 AC: 15 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	-0.79
CADD	Benign	0.19
DANN	Benign	0.79
PhyloP100		-0.77
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: rs79018048; hg19: chr2-219940946;