1-156624121-A-G

Position:

• chr1-156624121-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021817.3(HAPLN2):​c.400A>G​(p.Ile134Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. I134L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1455552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAPLN2	NM_021817.3	c.400A>G	p.Ile134Val	missense_variant	4/7	ENST00000255039.6
HAPLN2	XM_011509853.3	c.400A>G	p.Ile134Val	missense_variant	4/7
HAPLN2	XM_017002020.2	c.400A>G	p.Ile134Val	missense_variant	5/8
HAPLN2	XM_047427123.1	c.533A>G	p.His178Arg	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAPLN2	ENST00000255039.6	c.400A>G	p.Ile134Val	missense_variant	4/7	1	NM_021817.3	P1
HAPLN2	ENST00000456112.1	c.400A>G	p.Ile134Val	missense_variant	4/5	5
HAPLN2	ENST00000494218.1	n.58A>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.400A>G (p.I134V) alteration is located in exon 4 (coding exon 2) of the HAPLN2 gene. This alteration results from a A to G substitution at nucleotide position 400, causing the isoleucine (I) at amino acid position 134 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.78	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.069
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.033	D;T
Polyphen		0.0030	B;.
Vest4		0.14
MutPred		0.59		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.46
MPC		0.66
ClinPred		0.51	D
GERP RS		-0.22
Varity_R		0.20
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156593913;