rs7823648

Variant names:

• chr8-89943355-A-C
• rs7823648
• NM_002485.5:c.2082T>G

Your query was ambiguous. Multiple possible variants found:

• chr8-89943355-A-C
• chr8-89943355-A-G
• chr8-89943355-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002485.5(NBN):​c.2082T>G​(p.Pro694Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,603,120 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P694P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (113 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (113 hom.)
• Consequence: NBN NM_002485.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.84
• Publications: 4 publications found

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

NBN Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Orphanet, ClinGen
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• idiopathic aplastic anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 8-89943355-A-C is Benign according to our data. Variant chr8-89943355-A-C is described in ClinVar as Benign. ClinVar VariationId is 140767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0721 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002485.5. 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
	NBN	NM_002485.5	MANE Select	c.2082T>G	p.Pro694Pro	synonymous	Exon 14 of 16	NP_002476.2
	NBN	NM_001024688.3		c.1836T>G	p.Pro612Pro	synonymous	Exon 15 of 17	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.1836T>G	p.Pro612Pro	synonymous	Exon 14 of 16	NP_001427308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.2082T>G	p.Pro694Pro	synonymous	Exon 14 of 16	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.2082T>G	p.Pro694Pro	synonymous	Exon 14 of 15	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.2082T>G	p.Pro694Pro	synonymous	Exon 14 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3284 AN: 152170 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.0743

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00612 AC: 1537 AN: 251278 AF XY: 0.00434

Gnomad AFR exome AF: 0.0792

Gnomad AMR exome AF: 0.00396

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00231 AC: 3358 AN: 1450832 Hom.: 113 Cov.: 31 AF XY: 0.00202 AC XY: 1456 AN XY: 722576

African (AFR) AF: 0.0760 AC: 2518 AN: 33112

American (AMR) AF: 0.00438 AC: 196 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00556 AC: 145 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5750

European-Non Finnish (NFE) AF: 0.000143 AC: 158 AN: 1102190

Other (OTH) AF: 0.00511 AC: 307 AN: 60046

GnomAD4 genome AF: 0.0216 AC: 3290 AN: 152288 Hom.: 113 Cov.: 32 AF XY: 0.0209 AC XY: 1556 AN XY: 74484

African (AFR) AF: 0.0743 AC: 3085 AN: 41544

American (AMR) AF: 0.00817 AC: 125 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68022

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00710 Hom.: 68

Bravo AF: 0.0252

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Microcephaly, normal intelligence and immunodeficiency (4)
-	-	4	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Acute lymphoid leukemia (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.2
DANN	Benign	0.78
PhyloP100		1.8
Mutation Taster		=89/11	polymorphism (auto)

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: rs7823648; hg19: chr8-90955583; COSMIC: COSV104545433;