Genetic Variant AGER:p.Cys301Ser (chr6-32182309-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP4_StrongBP6BS2

The NM_001136.5(AGER):c.902G>C(p.Cys301Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,612,668 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 8 hom. )

Consequence

AGER
NM_001136.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.99

Publications

7 publications found

Variant links:

Genes affected

AGER (HGNC:320): (advanced glycosylation end-product specific receptor) The advanced glycosylation end product (AGE) receptor encoded by this gene is a member of the immunoglobulin superfamily of cell surface receptors. It is a multiligand receptor, and besides AGE, interacts with other molecules implicated in homeostasis, development, and inflammation, and certain diseases, such as diabetes and Alzheimer's disease. Many alternatively spliced transcript variants encoding different isoforms, as well as non-protein-coding variants, have been described for this gene (PMID:18089847). [provided by RefSeq, May 2011]

AGER links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.02679661).

BP6

Variant 6-32182309-C-G is Benign according to our data. Variant chr6-32182309-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 710266.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGER	NM_001136.5	MANE Select	c.902G>C	p.Cys301Ser	missense	Exon 8 of 11	NP_001127.1	Q15109-1
AGER	NM_001206929.2		c.950G>C	p.Cys317Ser	missense	Exon 8 of 11	NP_001193858.1	Q15109-6
AGER	NM_001206932.2		c.860G>C	p.Cys287Ser	missense	Exon 8 of 11	NP_001193861.1	Q15109-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGER	ENST00000375076.9	TSL:1 MANE Select	c.902G>C	p.Cys301Ser	missense	Exon 8 of 11	ENSP00000364217.4	Q15109-1
AGER	ENST00000375069.7	TSL:1	c.950G>C	p.Cys317Ser	missense	Exon 8 of 11	ENSP00000364210.4	Q15109-6
AGER	ENST00000438221.6	TSL:1	c.950G>C	p.Cys317Ser	missense	Exon 8 of 10	ENSP00000387887.2	Q15109-4

Frequencies

GnomAD3 genomes

AF:

0.00151

AC:

229

AN:

151926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00531

Gnomad ASJ

AF:

0.0283

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000530

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00215

AC:

530

AN:

246258

AF XY:

0.00208

show subpopulations

Gnomad AFR exome

AF:

0.000199

Gnomad AMR exome

AF:

0.00351

Gnomad ASJ exome

AF:

0.0307

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000669

Gnomad OTH exome

AF:

0.00379

GnomAD4 exome

AF:

0.00101

AC:

1474

AN:

1460624

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

727

AN XY:

726626

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.00349

AC:

156

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

798

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52166

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000305

AC:

339

AN:

1112006

Other (OTH)

AF:

0.00277

AC:

167

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

192

289

385

481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00151

AC:

229

AN:

152044

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

135

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41464

American (AMR)

AF:

0.00530

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0283

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000530

AC:

AN:

67976

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00246

Hom.:

Bravo

AF:

0.00165

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000332

AC:

ESP6500EA

AF:

0.000554

AC:

ExAC

AF:

0.00147

AC:

173

EpiCase

AF:

0.000709

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.082

MetaRNN

Benign

0.027

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

4.2

PhyloP100

4.0

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.79

Gain of disorder (P = 0.0304)

MVP

0.90

MPC

0.73

ClinPred

0.18

GERP RS

5.7

Varity_R

0.70

gMVP

0.93

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over