Genetic Variant CD96:p.Thr264Lys (chr3-111585362-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_005816.5(CD96):c.791C>A(p.Thr264Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. T264M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CD96
NM_005816.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.65

Publications

6 publications found

Variant links:

Genes affected

CD96 (HGNC:16892): (CD96 molecule) The protein encoded by this gene belongs to the immunoglobulin superfamily. It is a type I membrane protein. The protein may play a role in the adhesive interactions of activated T and NK cells during the late phase of the immune response. It may also function in antigen presentation. Alternative splicing generates multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2016]

CD96 Gene-Disease associations (from GenCC):

C syndrome
Inheritance: AD, Unknown, AR Classification: LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

CD96 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-111585362-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 4640.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.15481901).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005816.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD96	NM_005816.5	MANE Select	c.791C>A	p.Thr264Lys	missense	Exon 5 of 14	NP_005807.1	P40200-2
CD96	NM_198196.3		c.839C>A	p.Thr280Lys	missense	Exon 6 of 15	NP_937839.1	P40200-1
CD96	NM_001410800.1		c.791C>A	p.Thr264Lys	missense	Exon 5 of 14	NP_001397729.1	E9PEJ1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD96	ENST00000352690.9	TSL:1 MANE Select	c.791C>A	p.Thr264Lys	missense	Exon 5 of 14	ENSP00000342040.3	P40200-2
CD96	ENST00000283285.10	TSL:1	c.839C>A	p.Thr280Lys	missense	Exon 6 of 15	ENSP00000283285.5	P40200-1
CD96	ENST00000438817.6	TSL:1	c.791C>A	p.Thr264Lys	missense	Exon 5 of 8	ENSP00000389801.2	Q8WUE2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724638

African (AFR)

AF:

0.00

AC:

AN:

33352

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106558

Other (OTH)

AF:

0.00

AC:

AN:

60192

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.24

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.039

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.64

M_CAP

Benign

0.0056

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.4

PhyloP100

-1.7

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

REVEL

Benign

0.037

Sift

Benign

0.12

Sift4G

Benign

0.088

Polyphen

0.0040

Vest4

0.50

MutPred

0.66

Gain of ubiquitination at T280 (P = 0.0138)

MVP

0.55

MPC

0.067

ClinPred

0.099

GERP RS

-5.3

Varity_R

0.072

gMVP

0.36

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over