rs669

Positions:

• chr12-9079672-T-C

Variant summary

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

The ENST00000318602.12(A2M):​c.2998A>G​(p.Ile1000Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,612,050 control chromosomes in the GnomAD database, including 90,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8339 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82238 hom.)
• Consequence: A2M ENST00000318602.12 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.907

Genes affected

A2M (HGNC:7): (alpha-2-macroglobulin) The protein encoded by this gene is a protease inhibitor and cytokine transporter. It uses a bait-and-trap mechanism to inhibit a broad spectrum of proteases, including trypsin, thrombin and collagenase. It can also inhibit inflammatory cytokines, and it thus disrupts inflammatory cascades. Mutations in this gene are a cause of alpha-2-macroglobulin deficiency. This gene is implicated in Alzheimer's disease (AD) due to its ability to mediate the clearance and degradation of A-beta, the major component of beta-amyloid deposits. A related pseudogene, which is also located on the p arm of chromosome 12, has been identified. [provided by RefSeq, Nov 2016]

KLRG1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035947263).
• BP6: Variant 12-9079672-T-C is Benign according to our data. Variant chr12-9079672-T-C is described in ClinVar as [Benign]. Clinvar id is 18171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-9079672-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2M	NM_000014.6	c.2998A>G	p.Ile1000Val	missense_variant	24/36	ENST00000318602.12	NP_000005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2M	ENST00000318602.12	c.2998A>G	p.Ile1000Val	missense_variant	24/36	1	NM_000014.6	ENSP00000323929	P1
A2M	ENST00000542567.1	n.353A>G		non_coding_transcript_exon_variant	3/5	4
A2M	ENST00000543436.2	n.451+10240A>G		intron_variant, non_coding_transcript_variant		5
A2M	ENST00000545828.1	n.349-6951A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49127 AN: 151996 Hom.: 8331 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.0809

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.300

GnomAD3 exomes AF: 0.310 AC: 77045 AN: 248678 Hom.: 13020 AF XY: 0.303 AC XY: 40840 AN XY: 134838

Gnomad AFR exome AF: 0.307

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.0878

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.341

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.329 AC: 479974 AN: 1459936 Hom.: 82238 Cov.: 35 AF XY: 0.324 AC XY: 235261 AN XY: 726318

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.383

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.0754

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.406

Gnomad4 NFE exome AF: 0.347

Gnomad4 OTH exome AF: 0.307

GnomAD4 genome AF: 0.323 AC: 49174 AN: 152114 Hom.: 8339 Cov.: 32 AF XY: 0.324 AC XY: 24077 AN XY: 74362

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.359

Gnomad4 ASJ AF: 0.245

Gnomad4 EAS AF: 0.0811

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.347

Gnomad4 OTH AF: 0.299

Alfa AF: 0.326 Hom.: 20401

Bravo AF: 0.318

TwinsUK AF: 0.337 AC: 1251

ALSPAC AF: 0.345 AC: 1329

ESP6500AA AF: 0.302 AC: 1235

ESP6500EA AF: 0.328 AC: 2776

ExAC AF: 0.308 AC: 37285

Asia WGS AF: 0.172 AC: 600 AN: 3478

EpiCase AF: 0.330

EpiControl AF: 0.316

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2019	This variant is associated with the following publications: (PMID: 9811940, 24039871) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

ALPHA-2-MACROGLOBULIN POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Mar 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.74
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.038
Sift	Benign	0.15	T
Sift4G	Benign	0.28	T
Polyphen		0.019	B
Vest4		0.072
MPC		0.18
ClinPred		0.0021	T
GERP RS		0.089
Varity_R		0.074
gMVP		0.12

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: rs669; hg19: chr12-9232268; COSMIC: COSV59386644; COSMIC: COSV59386644;