Genetic Variant NM_020404.3:c.2132C>G (chr11-66314896-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020404.3(CD248):c.2132C>G(p.Thr711Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,038 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T711I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CD248
NM_020404.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.95

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD248	NM_020404.3 link	c.2132C>G	p.Thr711Ser	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.2132C>G	p.Thr711Ser	missense_variant	Exon 1 of 1	6	NM_020404.3	ENSP00000308117.3	Q9HCU0-1
ENSG00000254458	ENST00000534065.1 link	n.140+1904G>C		intron_variant	Intron 1 of 1	4
ENSG00000254756	ENST00000820635.1 link	n.134+2733G>C		intron_variant	Intron 1 of 3
ENSG00000254756	ENST00000820636.1 link	n.96+2733G>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726222

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86022

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111484

Other (OTH)

AF:

0.00

AC:

AN:

60318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

0.14

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.69

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.47

MetaSVM

Uncertain

-0.082

MutationAssessor

Benign

1.1

PhyloP100

4.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.37

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Polyphen

0.80

Vest4

0.55

MutPred

0.28

Loss of sheet (P = 0.0817);

MVP

0.75

MPC

1.1

ClinPred

0.82

GERP RS

3.2

Varity_R

0.14

gMVP

0.60

Mutation Taster

=85/15

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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NM_020404.3:c.2132C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over