1-156624136-G-T

Position:

chr1-156624136-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021817.3(HAPLN2):c.415G>T(p.Val139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,613,516 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 40 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 30 hom. )

Consequence

HAPLN2
NM_021817.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018447638).

BP6

Variant 1-156624136-G-T is Benign according to our data. Variant chr1-156624136-G-T is described in ClinVar as [Benign]. Clinvar id is 782390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1817/152278) while in subpopulation AFR AF= 0.0418 (1735/41548). AF 95% confidence interval is 0.0401. There are 40 homozygotes in gnomad4. There are 856 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HAPLN2	NM_021817.3 linkuse as main transcript	c.415G>T	p.Val139Leu	missense_variant	4/7	ENST00000255039.6
HAPLN2	XM_011509853.3 linkuse as main transcript	c.415G>T	p.Val139Leu	missense_variant	4/7
HAPLN2	XM_017002020.2 linkuse as main transcript	c.415G>T	p.Val139Leu	missense_variant	5/8
HAPLN2	XM_047427123.1 linkuse as main transcript	c.548G>T	p.Arg183Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HAPLN2	ENST00000255039.6 linkuse as main transcript	c.415G>T	p.Val139Leu	missense_variant	4/7	1	NM_021817.3	P1
HAPLN2	ENST00000456112.1 linkuse as main transcript	c.415G>T	p.Val139Leu	missense_variant	4/5	5
HAPLN2	ENST00000494218.1 linkuse as main transcript	n.73G>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1819

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0419

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

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:

0.0000588

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00300

AC:

732

AN:

244292

Hom.:

AF XY:

0.00215

AC XY:

286

AN XY:

133158

show subpopulations

Gnomad AFR exome

AF:

0.0411

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000926

Gnomad OTH exome

AF:

0.000995

GnomAD4 exome

AF:

0.00122

AC:

1777

AN:

1461238

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

747

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.0443

Gnomad4 AMR exome

AF:

0.00184

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.00242

GnomAD4 genome

AF:

0.0119

AC:

1817

AN:

152278

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

856

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0418

Gnomad4 AMR

AF:

0.00412

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00203

Hom.:

Bravo

AF:

0.0135

ESP6500AA

AF:

0.0372

AC:

162

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.00356

AC:

431

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.58

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.51

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.040

Sift

Benign

0.29

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.0030

B;.

Vest4

0.11

MutPred

0.56

Gain of catalytic residue at V139 (P = 0.1388);Gain of catalytic residue at V139 (P = 0.1388);

MVP

0.21

MPC

0.81

ClinPred

0.0038

GERP RS

1.9

Varity_R

0.14

gMVP

0.68

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over