12-9093580-CTATGG-C

Position:

• chr12-9093580-CTATGG-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_000014.6(A2M):​c.2126-6_2126-2delCCATA variant causes a splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,562,510 control chromosomes in the GnomAD database, including 17,998 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2086 hom., cov: 28)
  • Exomes 𝑓: 0.15 (15912 hom.)
• Consequence: A2M NM_000014.6 splice_acceptor, splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.64

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:6380): (killer cell lectin like receptor G1) Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. The protein encoded by this gene belongs to the killer cell lectin-like receptor (KLR) family, which is a group of transmembrane proteins preferentially expressed in NK cells. Studies in mice suggested that the expression of this gene may be regulated by MHC class I molecules. [provided by RefSeq, Jun 2016]

A2M (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.025762713 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.7, offset of 0 (no position change), new splice context is: atgtcttcttcctcactcAGagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 12-9093580-CTATGG-C is Benign according to our data. Variant chr12-9093580-CTATGG-C is described in ClinVar as [Benign]. Clinvar id is 402328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A2M	NM_000014.6	c.2126-6_2126-2delCCATA		splice_acceptor_variant, splice_region_variant, intron_variant		ENST00000318602.12	NP_000005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A2M	ENST00000318602.12	c.2126-6_2126-2delCCATA		splice_acceptor_variant, splice_region_variant, intron_variant		1	NM_000014.6	ENSP00000323929.8
A2M	ENST00000545828.1	n.348+7965_348+7969delCCATA		intron_variant		4
A2M	ENST00000546069.1	n.*223-6_*223-2delCCATA		splice_acceptor_variant, splice_region_variant, intron_variant		5		ENSP00000438599.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24315 AN: 151112 Hom.: 2073 Cov.: 28

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0985

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.137 AC: 31026 AN: 226034 Hom.: 2267 AF XY: 0.142 AC XY: 17376 AN XY: 122624

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.0797

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.0322

Gnomad SAS exome AF: 0.165

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.146 AC: 206724 AN: 1411282 Hom.: 15912 AF XY: 0.148 AC XY: 103436 AN XY: 700704

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0830

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.0345

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.151

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.161 AC: 24348 AN: 151228 Hom.: 2086 Cov.: 28 AF XY: 0.157 AC XY: 11590 AN XY: 73832

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.0365

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.0985

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.156

Alfa AF: 0.161 Hom.: 329

Bravo AF: 0.162

Asia WGS AF: 0.121 AC: 423 AN: 3478

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

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 305/2178=14% -

ALPHA-2-MACROGLOBULIN POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Aug 01, 1998

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2021

This variant is associated with the following publications: (PMID: 1717945, 24039871, 9697696, 11041282, 15130954, 32531432) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1799759; hg19: chr12-9246176;