12-6445462-G-A

Variant names:

• chr12-6445462-G-A
• rs25680
• NM_001242.5:c.175G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:4
• Conservation: PhyloP100: 0.872
• Publications: 52 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD27	NM_001242.5	MANE Select	c.175G>A	p.Ala59Thr	missense	Exon 2 of 6	NP_001233.2
	CD27	NM_001413263.1		c.175G>A	p.Ala59Thr	missense	Exon 2 of 7	NP_001400192.1
	CD27	NM_001413264.1		c.175G>A	p.Ala59Thr	missense	Exon 2 of 6	NP_001400193.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD27	ENST00000266557.4	TSL:1 MANE Select	c.175G>A	p.Ala59Thr	missense	Exon 2 of 6	ENSP00000266557.3
	CD27-AS1	ENST00000399492.6	TSL:1	n.484+1499C>T		intron	N/A
	CD27-AS1	ENST00000417058.6	TSL:1	n.813+1499C>T		intron	N/A

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

GnomAD2 exomes AF: 0.191 AC: 47909 AN: 251384 AF XY: 0.200

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 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

African (AFR) AF: 0.167 AC: 5587 AN: 33476

American (AMR) AF: 0.101 AC: 4518 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3955 AN: 26134

East Asian (EAS) AF: 0.0404 AC: 1603 AN: 39700

South Asian (SAS) AF: 0.286 AC: 24657 AN: 86258

European-Finnish (FIN) AF: 0.176 AC: 9407 AN: 53376

Middle Eastern (MID) AF: 0.206 AC: 1190 AN: 5768

European-Non Finnish (NFE) AF: 0.235 AC: 261245 AN: 1111906

Other (OTH) AF: 0.216 AC: 13045 AN: 60394

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

African (AFR) AF: 0.169 AC: 7029 AN: 41502

American (AMR) AF: 0.144 AC: 2200 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 530 AN: 3470

East Asian (EAS) AF: 0.0569 AC: 295 AN: 5180

South Asian (SAS) AF: 0.294 AC: 1418 AN: 4822

European-Finnish (FIN) AF: 0.165 AC: 1743 AN: 10578

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15609 AN: 67964

Other (OTH) AF: 0.177 AC: 373 AN: 2110

Alfa AF: 0.212 Hom.: 16403

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.87
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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