Variant chr1-156624121-A-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_021817.3(HAPLN2):c.400A>C(p.Ile134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I134M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HAPLN2
NM_021817.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.118

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 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=0.048675716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HAPLN2	NM_021817.3 linkuse as main transcript	c.400A>C	p.Ile134Leu	missense_variant	4/7	ENST00000255039.6
HAPLN2	XM_011509853.3 linkuse as main transcript	c.400A>C	p.Ile134Leu	missense_variant	4/7
HAPLN2	XM_017002020.2 linkuse as main transcript	c.400A>C	p.Ile134Leu	missense_variant	5/8
HAPLN2	XM_047427123.1 linkuse as main transcript	c.533A>C	p.His178Pro	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HAPLN2	ENST00000255039.6 linkuse as main transcript	c.400A>C	p.Ile134Leu	missense_variant	4/7	1	NM_021817.3	P1
HAPLN2	ENST00000456112.1 linkuse as main transcript	c.400A>C	p.Ile134Leu	missense_variant	4/5	5
HAPLN2	ENST00000494218.1 linkuse as main transcript	n.58A>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000817

AC:

AN:

244922

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133428

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461380

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.400A>C (p.I134L) alteration is located in exon 4 (coding exon 2) of the HAPLN2 gene. This alteration results from a A to C substitution at nucleotide position 400, causing the isoleucine (I) at amino acid position 134 to be replaced by a leucine (L). 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

Benign

0.085

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.8

DANN

Benign

0.65

DEOGEN2

Benign

0.059

T;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.0068

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

0.60

PrimateAI

Uncertain

0.53

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.093

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.15

MutPred

0.63

Gain of catalytic residue at I134 (P = 0.0472);Gain of catalytic residue at I134 (P = 0.0472);

MVP

0.38

MPC

0.78

ClinPred

0.044

GERP RS

-0.22

Varity_R

0.12

gMVP

0.45

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