2-219077217-C-T

Variant names:

• chr2-219077217-C-T
• rs115483157
• NM_024782.3:c.825+29G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024782.3(NHEJ1):​c.825+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,549,942 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.018 (259 hom.)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.54
• Publications: 3 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=-0.85).
• BP6: Variant 2-219077217-C-T is Benign according to our data. Variant chr2-219077217-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1200626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2168/152312) while in subpopulation NFE AF = 0.022 (1495/68028). AF 95% confidence interval is 0.021. There are 22 homozygotes in GnomAd4. There are 1042 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.825+29G>A		intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.840+29G>A		intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.825+29G>A		intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.1003+29G>A		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.825+29G>A		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1947+29G>A		intron_variant	Intron 16 of 16	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2169 AN: 152194 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0220

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0153 AC: 3847 AN: 251018 AF XY: 0.0154

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00790

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0292

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0181 AC: 25333 AN: 1397630 Hom.: 259 Cov.: 24 AF XY: 0.0177 AC XY: 12358 AN XY: 699372

African (AFR) AF: 0.00256 AC: 82 AN: 32082

American (AMR) AF: 0.00784 AC: 350 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 264 AN: 25800

East Asian (EAS) AF: 0.00 AC: 0 AN: 39370

South Asian (SAS) AF: 0.00602 AC: 511 AN: 84912

European-Finnish (FIN) AF: 0.0286 AC: 1527 AN: 53358

Middle Eastern (MID) AF: 0.0103 AC: 55 AN: 5328

European-Non Finnish (NFE) AF: 0.0205 AC: 21628 AN: 1053886

Other (OTH) AF: 0.0157 AC: 916 AN: 58272

GnomAD4 genome AF: 0.0142 AC: 2168 AN: 152312 Hom.: 22 Cov.: 32 AF XY: 0.0140 AC XY: 1042 AN XY: 74490

African (AFR) AF: 0.00262 AC: 109 AN: 41566

American (AMR) AF: 0.0105 AC: 161 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4826

European-Finnish (FIN) AF: 0.0281 AC: 298 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0220 AC: 1495 AN: 68028

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0201 Hom.: 41

Bravo AF: 0.0119

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 05, 2018

GeneDx

Significance: Likely 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	-0.85
CADD	Benign	0.18
DANN	Benign	0.71
PhyloP100		-1.5
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: rs115483157; hg19: chr2-219941939;