chr17-7101645-T-C

Position:

• chr17-7101645-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001201352.2(ASGR2):​c.851A>G​(p.Asp284Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ASGR2 NM_001201352.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

Genes affected

ASGR2 (HGNC:743): (asialoglycoprotein receptor 2) This gene encodes a subunit of the asialoglycoprotein receptor. This receptor is a transmembrane protein that plays a critical role in serum glycoprotein homeostasis by mediating the endocytosis and lysosomal degradation of glycoproteins with exposed terminal galactose or N-acetylgalactosamine residues. The asialoglycoprotein receptor may facilitate hepatic infection by multiple viruses including hepatitis B, and is also a target for liver-specific drug delivery. The asialoglycoprotein receptor is a hetero-oligomeric protein composed of major and minor subunits, which are encoded by different genes. The protein encoded by this gene is the less abundant minor subunit. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASGR2	NM_001201352.2	c.851A>G	p.Asp284Gly	missense_variant	9/9	ENST00000691900.1	NP_001188281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASGR2	ENST00000691900.1	c.851A>G	p.Asp284Gly	missense_variant	9/9		NM_001201352.2	ENSP00000510808.1
ASGR2	ENST00000355035.9	c.866A>G	p.Asp289Gly	missense_variant	9/9	1		ENSP00000347140.5
ASGR2	ENST00000446679.6	c.809A>G	p.Asp270Gly	missense_variant	8/8	1		ENSP00000405844.2
ASGR2	ENST00000254850.11	c.794A>G	p.Asp265Gly	missense_variant	9/9	1		ENSP00000254850.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2024

The c.866A>G (p.D289G) alteration is located in exon 9 (coding exon 8) of the ASGR2 gene. This alteration results from a A to G substitution at nucleotide position 866, causing the aspartic acid (D) at amino acid position 289 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.0056
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.8	H;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.022	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;B;D
Vest4		0.26
MutPred		0.94		Gain of MoRF binding (P = 0.0389);.;.;
MVP		0.20
ClinPred		0.90	D
GERP RS		3.7
Varity_R		0.60
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7004964;