rs35882952

Variant names:

• chr1-22863060-G-T
• rs35882952
• NM_017449.5:c.835G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-22863060-G-T
• chr1-22863060-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017449.5(EPHB2):​c.835G>T​(p.Ala279Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,614,160 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: EPHB2 NM_017449.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: 0.593
• Publications: 10 publications found

Genes affected

EPHB2 (HGNC:3393): (EPH receptor B2) This gene encodes a member of the Eph receptor family of receptor tyrosine kinase transmembrane glycoproteins. These receptors are composed of an N-terminal glycosylated ligand-binding domain, a transmembrane region and an intracellular kinase domain. They bind ligands called ephrins and are involved in diverse cellular processes including motility, division, and differentiation. A distinguishing characteristic of Eph-ephrin signaling is that both receptors and ligands are competent to transduce a signaling cascade, resulting in bidirectional signaling. This protein belongs to a subgroup of the Eph receptors called EphB. Proteins of this subgroup are distinguished from other members of the family by sequence homology and preferential binding affinity for membrane-bound ephrin-B ligands. Allelic variants are associated with prostate and brain cancer susceptibility. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]

MIR4253 (HGNC:38231): (microRNA 4253) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004200548).
• BP6: Variant 1-22863060-G-T is Benign according to our data. Variant chr1-22863060-G-T is described in ClinVar as Benign. ClinVar VariationId is 8533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017449.5. 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
	EPHB2	NM_017449.5	MANE Select	c.835G>T	p.Ala279Ser	missense	Exon 4 of 16	NP_059145.2	P29323-2
	EPHB2	NM_001309193.2		c.835G>T	p.Ala279Ser	missense	Exon 4 of 17	NP_001296122.1	P29323-1
	EPHB2	NM_004442.7		c.835G>T	p.Ala279Ser	missense	Exon 4 of 16	NP_004433.2	Q6NVW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB2	ENST00000374630.8	TSL:1 MANE Select	c.835G>T	p.Ala279Ser	missense	Exon 4 of 16	ENSP00000363761.3	P29323-2
	EPHB2	ENST00000400191.7	TSL:1	c.835G>T	p.Ala279Ser	missense	Exon 4 of 17	ENSP00000383053.3	P29323-1
	EPHB2	ENST00000374632.7	TSL:1	c.835G>T	p.Ala279Ser	missense	Exon 4 of 16	ENSP00000363763.3	P29323-3

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 576 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00107 AC: 270 AN: 251316 AF XY: 0.000898

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000363 AC: 530 AN: 1461890 Hom.: 2 Cov.: 31 AF XY: 0.000333 AC XY: 242 AN XY: 727248

African (AFR) AF: 0.0132 AC: 441 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112012

Other (OTH) AF: 0.000811 AC: 49 AN: 60396

GnomAD4 genome AF: 0.00379 AC: 577 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.00368 AC XY: 274 AN XY: 74452

African (AFR) AF: 0.0134 AC: 555 AN: 41544

American (AMR) AF: 0.000785 AC: 12 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00137 Hom.: 2

Bravo AF: 0.00450

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00116 AC: 141

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
1	-	-	Prostate cancer/brain cancer susceptibility (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N
PhyloP100		0.59
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.029
Sift	Benign	0.39	T
Sift4G	Benign	0.62	T
Polyphen		0.0090	B
Vest4		0.15
MVP		0.34
MPC		0.51
ClinPred		0.019	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.40
Mutation Taster		=92/8	polymorphism

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: rs35882952; hg19: chr1-23189553;