Genetic Variant HAPLN2:p.Arg231Gln (chr1-156624736-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021817.3(HAPLN2):c.692G>A(p.Arg231Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R231P) 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

Not reported in ClinVar

Conservation

PhyloP100: 0.855

Publications

0 publications found

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:

BCAN-AS2 (HGNC:56267): (BCAN antisense RNA 2)

BCAN-AS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061603248).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021817.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAPLN2	NM_021817.3	MANE Select	c.692G>A	p.Arg231Gln	missense	Exon 6 of 7	NP_068589.1	Q9GZV7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HAPLN2	ENST00000255039.6	TSL:1 MANE Select	c.692G>A	p.Arg231Gln	missense	Exon 6 of 7	ENSP00000255039.1	Q9GZV7
HAPLN2	ENST00000858239.1		c.734G>A	p.Arg245Gln	missense	Exon 6 of 7	ENSP00000528298.1
HAPLN2	ENST00000968562.1		c.734G>A	p.Arg245Gln	missense	Exon 6 of 7	ENSP00000638621.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1407160

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

AN XY:

697366

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32186

American (AMR)

AF:

0.00

AC:

AN:

37308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24316

East Asian (EAS)

AF:

0.00

AC:

AN:

38024

South Asian (SAS)

AF:

0.0000125

AC:

AN:

80104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38442

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5530

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1092834

Other (OTH)

AF:

0.00

AC:

AN:

58416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.066

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.71

M_CAP

Benign

0.0093

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.95

PhyloP100

0.85

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.2

REVEL

Benign

0.084

Sift

Benign

0.064

Sift4G

Benign

0.12

Polyphen

0.022

Vest4

0.15

MutPred

0.43

Gain of sheet (P = 0.0101)

MVP

0.22

MPC

0.90

ClinPred

0.84

GERP RS

-1.1

Varity_R

0.034

gMVP

0.57

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over