dbSNP rs149573918: HAPLN2:p.Val139Met (chr1-156624136-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021817.3(HAPLN2):c.415G>A(p.Val139Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V139L) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

HAPLN2
NM_021817.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.598

Variant links:

Genes affected

HAPLN2 (HGNC:17410): (hyaluronan and proteoglycan link protein 2) Predicted to enable hyaluronic acid binding activity. Predicted to be involved in central nervous system development and skeletal system development. Predicted to act upstream of or within establishment of blood-nerve barrier and extracellular matrix assembly. Predicted to be located in extracellular region. Predicted to be active in extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

HAPLN2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2656873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAPLN2	NM_021817.3 link	c.415G>A	p.Val139Met	missense_variant	Exon 4 of 7	ENST00000255039.6	NP_068589.1	Q9GZV7
HAPLN2	XM_011509853.3 link	c.415G>A	p.Val139Met	missense_variant	Exon 4 of 7		XP_011508155.1	Q9GZV7
HAPLN2	XM_017002020.2 link	c.415G>A	p.Val139Met	missense_variant	Exon 5 of 8		XP_016857509.1	Q9GZV7
HAPLN2	XM_047427123.1 link	c.548G>A	p.Arg183His	missense_variant	Exon 5 of 5		XP_047283079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HAPLN2	ENST00000255039.6 link	c.415G>A	p.Val139Met	missense_variant	Exon 4 of 7	1	NM_021817.3	ENSP00000255039.1	Q9GZV7
HAPLN2	ENST00000456112.1 link	c.415G>A	p.Val139Met	missense_variant	Exon 4 of 5	5		ENSP00000388835.1	Q5T3J1
HAPLN2	ENST00000494218.1 link	n.73G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2
HAPLN2	ENST00000482204.1 link	n.*222G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.84

T;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.084

Sift

Benign

0.099

T;D

Sift4G

Uncertain

0.058

T;T

Polyphen

0.89

P;.

Vest4

0.32

MutPred

0.59

Gain of disorder (P = 0.1177);Gain of disorder (P = 0.1177);

MVP

0.33

MPC

1.7

ClinPred

0.92

GERP RS

1.9

Varity_R

0.077

gMVP

0.69

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