12-103594490-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_017564.10(STAB2):c.311G>A(p.Arg104His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000811 in 1,613,634 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R104C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (1 hom.)
• Consequence: STAB2 NM_017564.10 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.59

Genes affected

STAB2 (HGNC:18629): (stabilin 2) This gene encodes a large, transmembrane receptor protein which may function in angiogenesis, lymphocyte homing, cell adhesion, or receptor scavenging. The protein contains 7 fasciclin, 15 epidermal growth factor (EGF)-like, and 2 laminin-type EGF-like domains as well as a C-type lectin-like hyaluronan-binding Link module. The protein is primarily expressed on sinusoidal endothelial cells of liver, spleen, and lymph node. The receptor has been shown to bind and endocytose ligands such as hyaluronan, low density lipoprotein, Gram-positive and Gram-negative bacteria, and advanced glycosylation end products. Supporting its possible role as a scavenger receptor, the protein has been shown to cycle between the plasma membrane and lysosomes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032396525).
• BP6: Variant 12-103594490-G-A is Benign according to our data. Variant chr12-103594490-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2348901.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAB2	NM_017564.10	c.311G>A	p.Arg104His	missense_variant	3/69	ENST00000388887.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAB2	ENST00000388887.7	c.311G>A	p.Arg104His	missense_variant	3/69	1	NM_017564.10	P1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000438 AC: 110 AN: 251214 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000766

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000848 AC: 1240 AN: 1461466 Hom.: 1 Cov.: 31 AF XY: 0.000875 AC XY: 636 AN XY: 727048

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74336

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000669 Hom.: 0

Bravo AF: 0.000434

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000493

EpiControl AF: 0.000890

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	11
Dann	Benign	0.75
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	3.7	N
REVEL	Benign	0.052
Sift	Benign	0.55	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.23
MPC		0.095
ClinPred		0.036	T
GERP RS		3.3
Varity_R		0.024
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs151009841; hg19: chr12-103988268; COSMIC: COSV99063299; COSMIC: COSV99063299;