rs1799759

Variant names:

• chr12-9093580-CTATGG-C
• rs1799759
• NM_000014.6:c.2126-6_2126-2delCCATA

Your query was ambiguous. Multiple possible variants found:

• chr12-9093580-CTATGG-C
• chr12-9093580-CTATGG-CTATGGTATGG

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0259887 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000014.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2M	NM_000014.6	MANE Select	c.2126-6_2126-2delCCATA		splice_acceptor splice_region intron	N/A	NP_000005.3	P01023
	A2M	NM_001347423.2		c.2126-6_2126-2delCCATA		splice_acceptor splice_region intron	N/A	NP_001334352.2	P01023
	A2M	NM_001347424.2		c.1826-6_1826-2delCCATA		splice_acceptor splice_region intron	N/A	NP_001334353.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	A2M	ENST00000318602.12	TSL:1 MANE Select	c.2126-6_2126-2delCCATA		splice_acceptor splice_region intron	N/A	ENSP00000323929.8	P01023
	A2M	ENST00000891833.1		c.2264-6_2264-2delCCATA		splice_acceptor splice_region intron	N/A	ENSP00000561892.1
	A2M	ENST00000956132.1		c.2126-6_2126-2delCCATA		splice_acceptor splice_region intron	N/A	ENSP00000626191.1

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

GnomAD2 exomes AF: 0.137 AC: 31026 AN: 226034 AF XY: 0.142

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 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

African (AFR) AF: 0.211 AC: 6726 AN: 31802

American (AMR) AF: 0.0830 AC: 3265 AN: 39326

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4542 AN: 24692

East Asian (EAS) AF: 0.0345 AC: 1348 AN: 39020

South Asian (SAS) AF: 0.162 AC: 12754 AN: 78912

European-Finnish (FIN) AF: 0.106 AC: 5582 AN: 52714

Middle Eastern (MID) AF: 0.176 AC: 986 AN: 5606

European-Non Finnish (NFE) AF: 0.151 AC: 162787 AN: 1080802

Other (OTH) AF: 0.150 AC: 8734 AN: 58408

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

African (AFR) AF: 0.205 AC: 8452 AN: 41158

American (AMR) AF: 0.125 AC: 1896 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 680 AN: 3464

East Asian (EAS) AF: 0.0365 AC: 188 AN: 5146

South Asian (SAS) AF: 0.164 AC: 784 AN: 4786

European-Finnish (FIN) AF: 0.0985 AC: 1019 AN: 10344

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10783 AN: 67816

Other (OTH) AF: 0.156 AC: 327 AN: 2100

Alfa AF: 0.161 Hom.: 329

Bravo AF: 0.162

Asia WGS AF: 0.121 AC: 423 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	A2M POLYMORPHISM (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=47/53	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1799759; hg19: chr12-9246176; COSMIC: COSV59385144; COSMIC: COSV59385144;