chr14-70375717-G-A

Position:

chr14-70375717-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018373.3(SYNJ2BP):c.256C>T(p.Arg86Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

SYNJ2BP
NM_018373.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.05

Variant links:

Genes affected

SYNJ2BP (HGNC:18955): (synaptojanin 2 binding protein) Predicted to enable type II activin receptor binding activity. Involved in several processes, including negative regulation of endothelial cell migration; negative regulation of sprouting angiogenesis; and regulation of signal transduction. Located in mitochondrion. Is integral component of mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

SYNJ2BP links:

SYNJ2BP-COX16 (HGNC:48350): (SYNJ2BP-COX16 readthrough) This locus represents naturally occurring read-through transcription between the neighboring SYNJ2BP (synaptojanin 2 binding protein) and COX16 (COX16 cytochrome c oxidase assembly homolog (S. cerevisiae)) genes on chromosome 14. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. Alternate splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Feb 2011]

SYNJ2BP-COX16 links:

SYNJ2BP (HGNC:):

SYNJ2BP links:

COX16 (HGNC:20213): (cytochrome c oxidase assembly factor COX16) Involved in mitochondrial cytochrome c oxidase assembly. Is integral component of mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

COX16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNJ2BP	NM_018373.3 linkuse as main transcript	c.256C>T	p.Arg86Cys	missense_variant	3/4	ENST00000256366.6	NP_060843.2	P57105A0A024R670
SYNJ2BP-COX16	NM_001202547.2 linkuse as main transcript	c.256C>T	p.Arg86Cys	missense_variant	3/6		NP_001189476.1
SYNJ2BP-COX16	NM_001202548.2 linkuse as main transcript	c.256C>T	p.Arg86Cys	missense_variant	3/6		NP_001189477.1	A0A087WYV9
SYNJ2BP-COX16	NM_001202549.2 linkuse as main transcript	c.256C>T	p.Arg86Cys	missense_variant	3/5		NP_001189478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNJ2BP	ENST00000256366.6 linkuse as main transcript	c.256C>T	p.Arg86Cys	missense_variant	3/4	1	NM_018373.3	ENSP00000256366.4		P57105
SYNJ2BP-COX16	ENST00000621525.4 linkuse as main transcript	c.256C>T	p.Arg86Cys	missense_variant	3/6	2		ENSP00000482133.1		A0A087WYV9

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251240

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The c.256C>T (p.R86C) alteration is located in exon 3 (coding exon 3) of the SYNJ2BP-COX16 gene. This alteration results from a C to T substitution at nucleotide position 256, causing the arginine (R) at amino acid position 86 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

.;.;.;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.92

D;.;D;D

M_CAP

Benign

0.051

MetaRNN

Uncertain

0.70

D;D;D;D

MetaSVM

Benign

-0.61

MutationAssessor

Pathogenic

2.9

.;.;.;M

MutationTaster

Benign

1.0

PROVEAN

Pathogenic

-5.2

.;.;.;D

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

.;.;.;D

Sift4G

Pathogenic

0.0010

D;.;.;D

Polyphen

1.0

.;.;.;D

Vest4

0.54

MVP

0.59

MPC

0.97

ClinPred

0.99

GERP RS

5.6

Varity_R

0.71

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over