2-219146736-G-C

Variant names:

• chr2-219146736-G-C
• NM_024782.3:c.532C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_024782.3(NHEJ1):​c.532C>G​(p.Arg178Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NHEJ1 NM_024782.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.27

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 4 ACMG points.

• PM1: In a mutagenesis_site Impaired ability to repair double-strand breaks (DSBs). Does not affect interaction with XRCC4. Does not affect ability to participate in V(D)J recombination. (size 0) in uniprot entity NHEJ1_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.532C>G	p.Arg178Gly	missense_variant, splice_region_variant	Exon 5 of 8	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.532C>G	p.Arg178Gly	missense_variant, splice_region_variant	Exon 5 of 8		NP_001364428.1
NHEJ1	NM_001377498.1	c.532C>G	p.Arg178Gly	missense_variant, splice_region_variant	Exon 5 of 8		NP_001364427.1
NHEJ1	NR_165304.1	n.628C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.532C>G	p.Arg178Gly	missense_variant, splice_region_variant	Exon 5 of 8	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1654C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 17	2		ENSP00000320919.3
ENSG00000280537	ENST00000318673.6	n.*1654C>G		3_prime_UTR_variant	Exon 14 of 17	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	.;T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	L;L;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;.
Polyphen		1.0	.;D;.;.
Vest4		0.85
MutPred		0.39		Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);.;Loss of stability (P = 0.0251);
MVP		0.89
MPC		0.068
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.54
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-220011458;