rs25680

chr12-6445462-G-Achr12-6445462-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001242.5(CD27):c.175G>A(p.Ala59Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,613,860 control chromosomes in the GnomAD database, including 41,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (3005 hom., cov: 31)
  • Exomes 𝑓: 0.22 (38000 hom.)
• Consequence: CD27 NM_001242.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.872

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044418573).
• BP6: Variant 12-6445462-G-A is Benign according to our data. Variant chr12-6445462-G-A is described in ClinVar as [Benign]. Clinvar id is 1168241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD27	NM_001242.5	c.175G>A	p.Ala59Thr	missense_variant	2/6	ENST00000266557.4
CD27-AS1	NR_015382.2	n.1516+1499C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD27	ENST00000266557.4	c.175G>A	p.Ala59Thr	missense_variant	2/6	1	NM_001242.5	P1
CD27-AS1	ENST00000689782.1	n.459+1499C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29458 AN: 152006 Hom.: 3008 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0568

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.179

GnomAD3 exomes AF: 0.191 AC: 47909 AN: 251384 Hom.: 5234 AF XY: 0.200 AC XY: 27158 AN XY: 135862

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.0938

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.0590

Gnomad SAS exome AF: 0.288

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.222 AC: 325207 AN: 1461736 Hom.: 38000 Cov.: 34 AF XY: 0.225 AC XY: 163421 AN XY: 727180

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.0404

Gnomad4 SAS exome AF: 0.286

Gnomad4 FIN exome AF: 0.176

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.194 AC: 29443 AN: 152124 Hom.: 3005 Cov.: 31 AF XY: 0.191 AC XY: 14180 AN XY: 74370

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.0569

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.177

Alfa AF: 0.214 Hom.: 9174

Bravo AF: 0.186

TwinsUK AF: 0.235 AC: 872

ALSPAC AF: 0.255 AC: 981

ESP6500AA AF: 0.176 AC: 777

ESP6500EA AF: 0.230 AC: 1977

ExAC AF: 0.198 AC: 24007

Asia WGS AF: 0.173 AC: 604 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.217

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 24. Only high quality variants are reported. -

Lymphoproliferative syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	12
Dann	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.13
Sift	Benign	0.77	T
Sift4G	Benign	0.52	T
Polyphen		0.47	P
Vest4		0.11
MPC		0.52
ClinPred		0.018	T
GERP RS		2.7
Varity_R		0.083
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs25680; hg19: chr12-6554628; COSMIC: COSV56949811; COSMIC: COSV56949811;