2-219157604-G-C

Variant names:

• chr2-219157604-G-C
• rs113689741
• NM_024782.3:c.258C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024782.3(NHEJ1):​c.258C>G​(p.Asp86Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D86D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NHEJ1 NM_024782.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43

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]

ENSG00000280537 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0932287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.258C>G	p.Asp86Glu	missense_variant	Exon 3 of 8	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.258C>G	p.Asp86Glu	missense_variant	Exon 3 of 8		NP_001364428.1
NHEJ1	NM_001377498.1	c.258C>G	p.Asp86Glu	missense_variant	Exon 3 of 8		NP_001364427.1
NHEJ1	NR_165304.1	n.354C>G		non_coding_transcript_exon_variant	Exon 3 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.258C>G	p.Asp86Glu	missense_variant	Exon 3 of 8	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1380C>G		non_coding_transcript_exon_variant	Exon 12 of 17	2		ENSP00000320919.3
ENSG00000280537	ENST00000318673.6	n.*1380C>G		3_prime_UTR_variant	Exon 12 of 17	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.70
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.093	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M;M;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.079	T;D;D;T
Sift4G	Uncertain	0.018	D;D;D;.
Polyphen		0.029	.;B;.;.
Vest4		0.065
MutPred		0.49		Loss of ubiquitination at K85 (P = 0.1113);Loss of ubiquitination at K85 (P = 0.1113);.;Loss of ubiquitination at K85 (P = 0.1113);
MVP		0.42
MPC		0.048
ClinPred		0.28	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.076

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

Publications

LitVar

Other links and lift over

dbSNP: rs113689741; hg19: chr2-220022326;