1-156624121-A-C

Variant names:

• chr1-156624121-A-C
• rs1391990049
• NM_021817.3:c.400A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.118

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]

ACMG classification

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 rank	MANE	Protein	UniProt
HAPLN2	NM_021817.3	c.400A>C	p.Ile134Leu	missense_variant	Exon 4 of 7	ENST00000255039.6	NP_068589.1
HAPLN2	XM_011509853.3	c.400A>C	p.Ile134Leu	missense_variant	Exon 4 of 7		XP_011508155.1
HAPLN2	XM_017002020.2	c.400A>C	p.Ile134Leu	missense_variant	Exon 5 of 8		XP_016857509.1
HAPLN2	XM_047427123.1	c.533A>C	p.His178Pro	missense_variant	Exon 5 of 5		XP_047283079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAPLN2	ENST00000255039.6	c.400A>C	p.Ile134Leu	missense_variant	Exon 4 of 7	1	NM_021817.3	ENSP00000255039.1
HAPLN2	ENST00000456112.1	c.400A>C	p.Ile134Leu	missense_variant	Exon 4 of 5	5		ENSP00000388835.1
HAPLN2	ENST00000494218.1	n.58A>C		non_coding_transcript_exon_variant	Exon 1 of 3	2
HAPLN2	ENST00000482204.1	n.*207A>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000817 AC: 2 AN: 244922 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133428

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: 2 AN: 1461380 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727032

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
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	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.53	T
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	T
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

Other links and lift over

dbSNP: rs1391990049; hg19: chr1-156593913;