rs6720495

Variant names:

• chr2-219078082-G-T
• rs6720495
• NM_024782.3:c.706+7C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-219078082-G-T
• chr2-219078082-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377499.1(NHEJ1):​c.713C>A​(p.Pro238His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,603,184 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (70 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (52 hom.)
• Consequence: NHEJ1 NM_001377499.1 missense
• Scores: Splicing: ADA: 0.00002503
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0730
• Publications: 1 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000280537 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002222687).
• BP6: Variant 2-219078082-G-T is Benign according to our data. Variant chr2-219078082-G-T is described in ClinVar as Benign. ClinVar VariationId is 138521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0539 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377499.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	NM_024782.3	MANE Select	c.706+7C>A		splice_region intron	N/A	NP_079058.1	Q9H9Q4-1
	NHEJ1	NM_001377499.1		c.713C>A	p.Pro238His	missense	Exon 6 of 8	NP_001364428.1	H7C0G7
	NHEJ1	NM_001377498.1		c.706+7C>A		splice_region intron	N/A	NP_001364427.1	Q9H9Q4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	ENST00000356853.10	TSL:1 MANE Select	c.706+7C>A		splice_region intron	N/A	ENSP00000349313.5	Q9H9Q4-1
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1828+7C>A		splice_region intron	N/A	ENSP00000320919.3	F8W735
	NHEJ1	ENST00000426304.6	TSL:3	c.713C>A	p.Pro238His	missense	Exon 6 of 8	ENSP00000394896.2	H7C0G7

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2454 AN: 152124 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00416 AC: 1045 AN: 251454 AF XY: 0.00315

Gnomad AFR exome AF: 0.0559

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00152 AC: 2201 AN: 1450942 Hom.: 52 Cov.: 28 AF XY: 0.00133 AC XY: 959 AN XY: 722610

African (AFR) AF: 0.0531 AC: 1767 AN: 33266

American (AMR) AF: 0.00347 AC: 155 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000814 AC: 7 AN: 86016

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5734

European-Non Finnish (NFE) AF: 0.0000789 AC: 87 AN: 1102056

Other (OTH) AF: 0.00293 AC: 176 AN: 60060

GnomAD4 genome AF: 0.0161 AC: 2453 AN: 152242 Hom.: 70 Cov.: 32 AF XY: 0.0153 AC XY: 1137 AN XY: 74436

African (AFR) AF: 0.0558 AC: 2316 AN: 41530

American (AMR) AF: 0.00654 AC: 100 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.0133 Hom.: 34

Bravo AF: 0.0181

ESP6500AA AF: 0.0538 AC: 237

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00516 AC: 627

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cernunnos-XLF deficiency (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.46
DANN	Benign	0.44
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.073
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.032
Sift	Benign	0.55	T
Sift4G	Benign	0.14	T
MVP		0.72
ClinPred		0.00066	T
GERP RS		0.77
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
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: rs6720495; hg19: chr2-219942804;