2-219076956-T-C

Variant names:

• chr2-219076956-T-C
• rs34828046
• NM_024782.3:c.825+290A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024782.3(NHEJ1):​c.825+290A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0323 in 152,266 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.032 (130 hom., cov: 32)
• Consequence: NHEJ1 NM_024782.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.843
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 2-219076956-T-C is Benign according to our data. Variant chr2-219076956-T-C is described in ClinVar as [Benign]. Clinvar id is 1237087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0323 (4921/152266) while in subpopulation NFE AF = 0.046 (3128/68028). AF 95% confidence interval is 0.0446. There are 130 homozygotes in GnomAd4. There are 2524 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 130 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.825+290A>G		intron_variant	Intron 7 of 7	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.840+290A>G		intron_variant	Intron 7 of 7		NP_001364428.1
NHEJ1	NM_001377498.1	c.825+290A>G		intron_variant	Intron 7 of 7		NP_001364427.1
NHEJ1	NR_165304.1	n.1003+290A>G		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.825+290A>G		intron_variant	Intron 7 of 7	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1947+290A>G		intron_variant	Intron 16 of 16	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4921 AN: 152148 Hom.: 130 Cov.: 32

Gnomad AFR AF: 0.00883

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0725

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.0254

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

GnomAD4 genome AF: 0.0323 AC: 4921 AN: 152266 Hom.: 130 Cov.: 32 AF XY: 0.0339 AC XY: 2524 AN XY: 74464

African (AFR) AF: 0.00881 AC: 366 AN: 41564

American (AMR) AF: 0.0300 AC: 458 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.00995 AC: 48 AN: 4826

European-Finnish (FIN) AF: 0.0725 AC: 768 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0460 AC: 3128 AN: 68028

Other (OTH) AF: 0.0251 AC: 53 AN: 2112

Alfa AF: 0.0364 Hom.: 35

Bravo AF: 0.0279

Asia WGS AF: 0.00606 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 17, 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
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.8
DANN	Benign	0.34
PhyloP100		-0.84
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: rs34828046; hg19: chr2-219941678;