8-89947815-G-A

Variant names:

• chr8-89947815-G-A
• rs13312938
• NM_002485.5:c.1914+9C>T

Variant summary

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

The NM_002485.5(NBN):​c.1914+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,521,356 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (77 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (45 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.0970
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-89947815-G-A is Benign according to our data. Variant chr8-89947815-G-A is described in ClinVar as Benign. ClinVar VariationId is 132686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0576 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.1914+9C>T		intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.1668+9C>T		intron	N/A	NP_001019859.1
	NBN	NM_001440379.1		c.1668+9C>T		intron	N/A	NP_001427308.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.1914+9C>T		intron	N/A	ENSP00000265433.4
	NBN	ENST00000697306.1		n.*946C>T		non_coding_transcript_exon	Exon 8 of 11	ENSP00000513241.1
	NBN	ENST00000697306.1		n.*946C>T		3_prime_UTR	Exon 8 of 11	ENSP00000513241.1

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2648 AN: 151938 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00388 AC: 861 AN: 221874 AF XY: 0.00273

Gnomad AFR exome AF: 0.0554

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000581

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00169 AC: 2317 AN: 1369300 Hom.: 45 Cov.: 23 AF XY: 0.00148 AC XY: 1009 AN XY: 683760

African (AFR) AF: 0.0591 AC: 1838 AN: 31110

American (AMR) AF: 0.00344 AC: 149 AN: 43254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25090

East Asian (EAS) AF: 0.00 AC: 0 AN: 38532

South Asian (SAS) AF: 0.000244 AC: 20 AN: 82086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51810

Middle Eastern (MID) AF: 0.00215 AC: 12 AN: 5590

European-Non Finnish (NFE) AF: 0.0000744 AC: 77 AN: 1034852

Other (OTH) AF: 0.00388 AC: 221 AN: 56976

GnomAD4 genome AF: 0.0176 AC: 2669 AN: 152056 Hom.: 77 Cov.: 32 AF XY: 0.0172 AC XY: 1282 AN XY: 74362

African (AFR) AF: 0.0596 AC: 2472 AN: 41498

American (AMR) AF: 0.0100 AC: 153 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67948

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00615 Hom.: 29

Bravo AF: 0.0194

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.71
PhyloP100		0.097
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs13312938; hg19: chr8-90960043; COSMIC: COSV105039112; COSMIC: COSV105039112;