chr6-32183666-C-T

Variant names:

• chr6-32183666-C-T
• rs2070600
• NM_001136.5:c.244G>A
• AGER p.Gly82Ser

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-7 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -7 classification points (ACMG Germline Pathogenicity v2019). BA1PP3

The NM_001136.5(AGER):c.244G>A (p.Gly82Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0561 (AC=90,557) in the gnomAD database across 1,613,010 control chromosomes, including 3,365 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.196. In-silico predictor (REVEL) classifies this variant as likely benign. Variant has been reported in ClinVar as Uncertain Significance (no review stars). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.039 (234 hom., cov: 33)
  • Exomes 𝑓: 0.058 (3131 hom.)
• Consequence: AGER NM_001136.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.46
• Publications: 239 publications found

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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support splicing impact — supporting computational evidence (PP3); Splicing verdict: pathogenic (Supporting).; Germline computational verdict: not pathogenic.
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1958 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AGER NM_001136.5	MANE Select	c.244G>A p.Gly82Ser	missense	Exon 3 of 11	Prot: NP_001127.1 UniProt:
	AGER NM_001206929.2		c.244G>A p.Gly82Ser	missense	Exon 3 of 11	Prot: NP_001193858.1 UniProt:
	AGER NM_001206932.2		c.202G>A p.Gly68Ser	missense	Exon 3 of 11	Prot: NP_001193861.1 UniProt:

AGER NM_001136.5

MANE Select

HGVSc / HGVSpc.244G>Ap.Gly82Ser

Exon rankExon 3 of 11

missense

Prot: NP_001127.1UniProt: Q15109-1

AGER NM_001206929.2

HGVSc / HGVSpc.244G>Ap.Gly82Ser

Exon rankExon 3 of 11

missense

Prot: NP_001193858.1UniProt: Q15109-6

AGER NM_001206932.2

HGVSc / HGVSpc.202G>Ap.Gly68Ser

Exon rankExon 3 of 11

missense

Prot: NP_001193861.1UniProt: Q15109-7

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AGER ENST00000375076.9	TSL:1MANE Select	c.244G>A p.Gly82Ser	missense	Exon 3 of 11	Prot: ENSP00000364217.4 UniProt:
	AGER ENST00000375069.7	TSL:1	c.244G>A p.Gly82Ser	missense	Exon 3 of 11	Prot: ENSP00000364210.4 UniProt:
	AGER ENST00000438221.6	TSL:1	c.244G>A p.Gly82Ser	missense	Exon 3 of 10	Prot: ENSP00000387887.2 UniProt:

AGER ENST00000375076.9

TSL:1MANE Select

HGVSc / HGVSpc.244G>Ap.Gly82Ser

Exon rankExon 3 of 11

missense

Prot: ENSP00000364217.4UniProt: Q15109-1

AGER ENST00000375069.7

TSL:1

HGVSc / HGVSpc.244G>Ap.Gly82Ser

Exon rankExon 3 of 11

missense

Prot: ENSP00000364210.4UniProt: Q15109-6

AGER ENST00000438221.6

TSL:1

HGVSc / HGVSpc.244G>Ap.Gly82Ser

Exon rankExon 3 of 10

missense

Prot: ENSP00000387887.2UniProt: Q15109-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0388	AC:5905	Hom:234	AN:152132	Cov:33
GnomAD2 exomes	AF: 0.0532	AC:13091	Hom:	AN:245924	Cov:
GnomAD4 exome	AF: 0.0580	AC:84662	Hom:3131	AN:1460760	Cov:36
GnomAD4 genome	AF: 0.0387	AC:5895	Hom:234	AN:152250	Cov:33
TOPMed (Bravo)	AF: 0.0339	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0429	AC:22085	Hom:767	AN:515214	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0179	AC:42	Hom:1	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0349	AC:294	Hom:	AN:8430	Cov:
GenomeAsia100K	AF: 0.104	AC:361	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.159	AC:1149	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0204	AC:41	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.153	AC:18670	Hom:1442	AN:122192	Cov:
Turkish Variome	AF: 0.0395	AC:61	Hom:2	AN:1546	Cov:
UK10K	AF: 0.0731	AC:553	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.254	AC:2272	Hom:268	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0514 *	494	9620	0.0484 *	505	10424
BipEx(Bipolar disorder (including schizoaffective))	0.0550	1562	28420	0.0564	1627	28844
Epi25(Epilepsy)	0.0534	2242	41958	0.0496	3317	66888
SCHEMA(Schizophrenia)	0.0837	10740	128388	0.0666	13132	197070

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	COPD, severe early onset (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	32
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.88	D
FuncVEP CTI	Benign	0.13
GPN-Star LLR	N/A	-4.6
GPN-Star score	N/A	4.6
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.2	T
Mutation Taster	N/A	87/13	polymorphism (auto)
MutationAssessor	Uncertain	2.8	M
PhyloP100	Benign	2.5
popEVE	Benign	-3.8
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.16
Sift	Benign	0.51	T
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.20
VESM-3B	Benign	-8.2

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_AG_spliceai	Pathogenic	0.73	Position offset: -2
Pangolin (max)	Pathogenic	0.53
Pangolin gain	Pathogenic	0.53	Position offset: -2
SpliceAI score (max)	Pathogenic	0.73	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2070600;

hg19: chr6-32151443;

COSMIC: COSV107496643;

COSMIC: COSV107496643;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar