11-66315067-T-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020404.3(CD248):​c.1961A>C​(p.Lys654Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,572,890 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CD248
NM_020404.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.592

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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.08812237).
BS2
High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CD248NM_020404.3 linkc.1961A>C p.Lys654Thr missense_variant Exon 1 of 1 ENST00000311330.4 NP_065137.1 Q9HCU0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CD248ENST00000311330.4 linkc.1961A>C p.Lys654Thr missense_variant Exon 1 of 1 6 NM_020404.3 ENSP00000308117.3 Q9HCU0-1
ENSG00000254458ENST00000534065.1 linkn.140+2075T>G intron_variant Intron 1 of 1 4
ENSG00000254756ENST00000820635.1 linkn.134+2904T>G intron_variant Intron 1 of 3
ENSG00000254756ENST00000820636.1 linkn.96+2904T>G intron_variant Intron 1 of 2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152080
Hom.:
0
Cov.:
32
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000464
AC:
1
AN:
215682
AF XY:
0.00000871
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000102
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000120
AC:
17
AN:
1420810
Hom.:
0
Cov.:
31
AF XY:
0.0000114
AC XY:
8
AN XY:
701630
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32734
American (AMR)
AF:
0.00
AC:
0
AN:
41582
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
22934
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39362
South Asian (SAS)
AF:
0.00
AC:
0
AN:
78976
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5556
European-Non Finnish (NFE)
AF:
0.0000138
AC:
15
AN:
1090428
Other (OTH)
AF:
0.0000341
AC:
2
AN:
58638
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152080
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74280
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41412
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68004
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000189

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 16, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1961A>C (p.K654T) alteration is located in exon 1 (coding exon 1) of the CD248 gene. This alteration results from a A to C substitution at nucleotide position 1961, causing the lysine (K) at amino acid position 654 to be replaced by a threonine (T). 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
0.10
BayesDel_addAF
Benign
-0.0062
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
0.40
DANN
Benign
0.95
DEOGEN2
Benign
0.071
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.071
N
LIST_S2
Benign
0.48
T
M_CAP
Benign
0.057
D
MetaRNN
Benign
0.088
T
MetaSVM
Benign
-0.63
T
MutationAssessor
Benign
1.0
L
PhyloP100
-0.59
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.0
N
REVEL
Benign
0.29
Sift
Uncertain
0.0030
D
Sift4G
Benign
0.42
T
Polyphen
0.0070
B
Vest4
0.26
MutPred
0.15
Loss of ubiquitination at K654 (P = 0.0051);
MVP
0.43
MPC
0.42
ClinPred
0.18
T
GERP RS
1.1
Varity_R
0.083
gMVP
0.22
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

Publications

Other links and lift over

dbSNP: rs780843035; hg19: chr11-66082538; API