Genetic Variant NM_003773.5:c.1351G>C (chr3-50318200-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003773.5(HYAL2):c.1351G>C(p.Glu451Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HYAL2
NM_003773.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.169

Variant links:

Genes affected

HYAL2 (HGNC:5321): (hyaluronidase 2) This gene encodes a weak acid-active hyaluronidase. The encoded protein is similar in structure to other more active hyaluronidases. Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan and fragments of hyaluronan are thought to be involved in cell proliferation, migration and differentiation. Although it was previously thought to be a lysosomal hyaluronidase that is active at a pH below 4, the encoded protein is likely a GPI-anchored cell surface protein. This hyaluronidase serves as a receptor for the oncogenic virus Jaagsiekte sheep retrovirus. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. This gene encodes two alternatively spliced transcript variants which differ only in the 5' UTR.[provided by RefSeq, Mar 2010]

HYAL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046842963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYAL2	NM_003773.5 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 4 of 4	ENST00000357750.9	NP_003764.3	Q12891
HYAL2	NM_033158.5 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 5 of 5		NP_149348.2	Q12891
HYAL2	XM_005265524.3 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 5 of 5		XP_005265581.1	Q12891
HYAL2	XM_005265525.3 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 4 of 4		XP_005265582.1	Q12891

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HYAL2	ENST00000357750.9 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 4 of 4	1	NM_003773.5	ENSP00000350387.4	Q12891
HYAL2	ENST00000395139.7 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 4 of 4	1		ENSP00000378571.3	Q12891
HYAL2	ENST00000447092.5 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 3 of 3	1		ENSP00000401853.1	Q12891
HYAL2	ENST00000442581.1 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 5 of 5	2		ENSP00000406657.1	Q12891

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249538

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135242

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460472

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726516

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.15

DANN

Benign

0.51

DEOGEN2

Benign

0.22

T;T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.56

.;.;.;T

M_CAP

Benign

0.0056

MetaRNN

Benign

0.047

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.26

N;N;N;N

REVEL

Benign

0.0070

Sift

Benign

0.59

T;T;T;T

Sift4G

Benign

0.57

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.046

MutPred

0.18

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.43

MPC

0.50

ClinPred

0.020

GERP RS

-5.3

Varity_R

0.053

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over