2-219146708-T-C

Position:

• chr2-219146708-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024782.3(NHEJ1):​c.560A>G​(p.Asn187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000551 in 1,611,718 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (3 hom.)
• Consequence: NHEJ1 NM_024782.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004739493).
• BP6: Variant 2-219146708-T-C is Benign according to our data. Variant chr2-219146708-T-C is described in ClinVar as [Benign]. Clinvar id is 568300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219146708-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000676 (103/152292) while in subpopulation NFE AF= 0.000603 (41/68020). AF 95% confidence interval is 0.000457. There are 1 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHEJ1	NM_024782.3	c.560A>G	p.Asn187Ser	missense_variant	5/8	ENST00000356853.10
NHEJ1	NM_001377499.1	c.560A>G	p.Asn187Ser	missense_variant	5/8
NHEJ1	NM_001377498.1	c.560A>G	p.Asn187Ser	missense_variant	5/8
NHEJ1	NR_165304.1	n.656A>G		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHEJ1	ENST00000356853.10	c.560A>G	p.Asn187Ser	missense_variant	5/8	1	NM_024782.3	P4

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000760 AC: 191 AN: 251426 Hom.: 0 AF XY: 0.000846 AC XY: 115 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000538 AC: 785 AN: 1459426 Hom.: 3 Cov.: 29 AF XY: 0.000566 AC XY: 411 AN XY: 726244

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74462

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00120 Hom.: 2

Bravo AF: 0.000684

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000626 AC: 76

EpiCase AF: 0.000709

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cernunnos-XLF deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.75
DEOGEN2	Benign	0.051	.;T;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.57	T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;.;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.63	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.43	T;T;T;T
Sift4G	Benign	0.65	T;T;T;.
Polyphen		0.0	.;B;.;.
Vest4		0.20
MVP		0.56
MPC		0.041
ClinPred		0.0091	T
GERP RS		1.6
Varity_R		0.056
gMVP		0.057

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: rs146861504; hg19: chr2-220011430;