12-6445126-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001242.5(CD27):c.31G>A(p.Val11Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000423 in 1,606,936 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CD27
NM_001242.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.32

Publications

0 publications found

Variant links:

Genes affected

CD27 (HGNC:11922): (CD27 molecule) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is required for generation and long-term maintenance of T cell immunity. It binds to ligand CD70, and plays a key role in regulating B-cell activation and immunoglobulin synthesis. This receptor transduces signals that lead to the activation of NF-kappaB and MAPK8/JNK. Adaptor proteins TRAF2 and TRAF5 have been shown to mediate the signaling process of this receptor. CD27-binding protein (SIVA), a proapoptotic protein, can bind to this receptor and is thought to play an important role in the apoptosis induced by this receptor. [provided by RefSeq, Jul 2008]

CD27 links:

CD27-AS1 (HGNC:43896): (CD27 antisense RNA 1)

CD27-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023220986).

BP6

Variant 12-6445126-G-A is Benign according to our data. Variant chr12-6445126-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1059188.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD27	NM_001242.5 link	c.31G>A	p.Val11Ile	missense_variant	Exon 1 of 6	ENST00000266557.4	NP_001233.2	P26842

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD27	ENST00000266557.4 link	c.31G>A	p.Val11Ile	missense_variant	Exon 1 of 6	1	NM_001242.5	ENSP00000266557.3		P26842

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000601

AC:

AN:

232842

AF XY:

0.0000633

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.0000622

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000771

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000440

AC:

AN:

1454768

Hom.:

Cov.:

AF XY:

0.0000470

AC XY:

AN XY:

723136

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33336

American (AMR)

AF:

0.0000233

AC:

AN:

42920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25910

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39518

South Asian (SAS)

AF:

0.0000352

AC:

AN:

85220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52936

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

0.0000469

AC:

AN:

1109300

Other (OTH)

AF:

0.0000832

AC:

AN:

60068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lymphoproliferative syndrome 2

Uncertain:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 11 of the CD27 protein (p.Val11Ile). This variant is present in population databases (rs772449872, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CD27-related conditions. ClinVar contains an entry for this variant (Variation ID: 1059188). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Jun 06, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.43

CADD

Benign

1.3

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.24

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.49

M_CAP

Benign

0.032

MetaRNN

Benign

0.023

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.32

PhyloP100

-1.3

PrimateAI

Benign

0.29

PROVEAN

Benign

0.050

REVEL

Benign

0.20

Sift

Benign

0.41

Sift4G

Benign

0.66

Polyphen

0.0

Vest4

0.030

MutPred

0.44

Gain of catalytic residue at W7 (P = 0.0018);

MVP

0.33

MPC

0.15

ClinPred

0.0051

GERP RS

-5.0

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.022

gMVP

0.31

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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12-6445126-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over