Genetic Variant CD248:p.Ile584Val (chr11-66315278-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020404.3(CD248):c.1750A>G(p.Ile584Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000519 in 1,540,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

CD248
NM_020404.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.31

Publications

0 publications found

Variant links:

Genes affected

CD248 (HGNC:18219): (CD248 molecule) Predicted to enable extracellular matrix binding activity and extracellular matrix protein binding activity. Predicted to be involved in cell migration. Predicted to act upstream of or within several processes, including anatomical structure regression; lymph node development; and positive regulation of endothelial cell apoptotic process. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

CD248 links:

ENSG00000254458 (HGNC:):

ENSG00000254458 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01760444).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD248	NM_020404.3 link	c.1750A>G	p.Ile584Val	missense_variant	Exon 1 of 1	ENST00000311330.4	NP_065137.1	Q9HCU0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CD248	ENST00000311330.4 link	c.1750A>G	p.Ile584Val	missense_variant	Exon 1 of 1	6	NM_020404.3	ENSP00000308117.3	Q9HCU0-1
ENSG00000254458	ENST00000534065.1 link	n.140+2286T>C		intron_variant	Intron 1 of 1	4
ENSG00000254756	ENST00000820635.1 link	n.134+3115T>C		intron_variant	Intron 1 of 3
ENSG00000254756	ENST00000820636.1 link	n.96+3115T>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000206

AC:

AN:

193862

AF XY:

0.0000390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000237

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000504

AC:

AN:

1389222

Hom.:

Cov.:

AF XY:

0.00000439

AC XY:

AN XY:

683126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31194

American (AMR)

AF:

0.00

AC:

AN:

34940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20966

East Asian (EAS)

AF:

0.000153

AC:

AN:

39104

South Asian (SAS)

AF:

0.0000134

AC:

AN:

74774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5384

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075726

Other (OTH)

AF:

0.00

AC:

AN:

57102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150910

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73618

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40970

American (AMR)

AF:

0.00

AC:

AN:

15158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000196

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67714

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1750A>G (p.I584V) alteration is located in exon 1 (coding exon 1) of the CD248 gene. This alteration results from a A to G substitution at nucleotide position 1750, causing the isoleucine (I) at amino acid position 584 to be replaced by a valine (V). 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

Benign

0.070

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.26

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.036

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.33

M_CAP

Benign

0.044

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.14

PhyloP100

-1.3

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.030

REVEL

Benign

0.17

Sift

Benign

0.79

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.038

MutPred

0.097

Loss of catalytic residue at P586 (P = 0.0309);

MVP

0.38

MPC

0.29

ClinPred

0.014

GERP RS

-8.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.048

Mutation Taster

=99/1

polymorphism

(source)

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

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11-66315278-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over