rs66949844

Variant names:

• chr19-51501537-G-GC
• rs66949844
• NM_053003.4:c.196dupG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_053003.4(SIGLEC12):​c.196dupG​(p.Ala66GlyfsTer50) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,613,324 control chromosomes in the GnomAD database, including 348,684 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.64 (31498 hom., cov: 0)
  • Exomes 𝑓: 0.66 (317186 hom.)
• Consequence: SIGLEC12 NM_053003.4 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.462
• Publications: 27 publications found

Genes affected

SIGLEC12 (HGNC:15482): (sialic acid binding Ig like lectin 12) Sialic acid-binding immunoglobulin-like lectins (SIGLECs) are a family of cell surface proteins belonging to the immunoglobulin superfamily. They mediate protein-carbohydrate interactions by selectively binding to different sialic acid moieties present on glycolipids and glycoproteins. This gene encodes a member of the SIGLEC3-like subfamily of SIGLECs. Members of this subfamily are characterized by an extracellular V-set immunoglobulin-like domain followed by two C2-set immunoglobulin-like domains, and the cytoplasmic tyrosine-based motifs ITIM and SLAM-like. The encoded protein, upon tyrosine phosphorylation, has been shown to recruit the Src homology 2 domain-containing protein-tyrosine phosphatases SHP1 and SHP2. It has been suggested that the protein is involved in the negative regulation of macrophage signaling by functioning as an inhibitory receptor. This gene is located in a cluster with other SIGLEC3-like genes on 19q13.4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 19-51501537-G-GC is Benign according to our data. Variant chr19-51501537-G-GC is described in ClinVar as Benign. ClinVar VariationId is 403443.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053003.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC12	NM_053003.4	MANE Select	c.196dupG	p.Ala66GlyfsTer50	frameshift	Exon 1 of 8	NP_443729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGLEC12	ENST00000291707.8	TSL:1 MANE Select	c.196dupG	p.Ala66GlyfsTer50	frameshift	Exon 1 of 8	ENSP00000291707.3
	SIGLEC12	ENST00000596742.1	TSL:1	n.196dupG		non_coding_transcript_exon	Exon 1 of 8	ENSP00000469791.1
	SIGLEC12	ENST00000942370.1		c.196dupG	p.Ala66GlyfsTer50	frameshift	Exon 1 of 7	ENSP00000612429.1

Frequencies

GnomAD3 genomes AF: 0.640 AC: 96901 AN: 151404 Hom.: 31491 Cov.: 0

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.653

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.666

GnomAD2 exomes AF: 0.645 AC: 162121 AN: 251402 AF XY: 0.642

Gnomad AFR exome AF: 0.591

Gnomad AMR exome AF: 0.773

Gnomad ASJ exome AF: 0.587

Gnomad EAS exome AF: 0.351

Gnomad FIN exome AF: 0.668

Gnomad NFE exome AF: 0.668

Gnomad OTH exome AF: 0.653

GnomAD4 exome AF: 0.656 AC: 958732 AN: 1461802 Hom.: 317186 Cov.: 81 AF XY: 0.655 AC XY: 476047 AN XY: 727202

African (AFR) AF: 0.585 AC: 19584 AN: 33480

American (AMR) AF: 0.764 AC: 34175 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 15387 AN: 26136

East Asian (EAS) AF: 0.375 AC: 14882 AN: 39700

South Asian (SAS) AF: 0.623 AC: 53707 AN: 86256

European-Finnish (FIN) AF: 0.662 AC: 35352 AN: 53418

Middle Eastern (MID) AF: 0.655 AC: 3777 AN: 5768

European-Non Finnish (NFE) AF: 0.668 AC: 743115 AN: 1111930

Other (OTH) AF: 0.642 AC: 38753 AN: 60394

GnomAD4 genome AF: 0.640 AC: 96931 AN: 151522 Hom.: 31498 Cov.: 0 AF XY: 0.637 AC XY: 47132 AN XY: 73994

African (AFR) AF: 0.591 AC: 24402 AN: 41262

American (AMR) AF: 0.720 AC: 10986 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2024 AN: 3458

East Asian (EAS) AF: 0.370 AC: 1893 AN: 5114

South Asian (SAS) AF: 0.637 AC: 3068 AN: 4814

European-Finnish (FIN) AF: 0.659 AC: 6907 AN: 10476

Middle Eastern (MID) AF: 0.654 AC: 191 AN: 292

European-Non Finnish (NFE) AF: 0.671 AC: 45513 AN: 67844

Other (OTH) AF: 0.660 AC: 1389 AN: 2104

Alfa AF: 0.649 Hom.: 5834

Bravo AF: 0.643

Asia WGS AF: 0.538 AC: 1870 AN: 3478

EpiCase AF: 0.670

EpiControl AF: 0.669

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.46
Mutation Taster		=176/24	polymorphism (auto)

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

Other links and lift over

dbSNP: rs66949844; hg19: chr19-52004791; COSMIC: COSV52459014; COSMIC: COSV52459014;