chr1-156623506-A-G

Position:

• chr1-156623506-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.16A>G​(p.Thr6Ala) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: -0.719

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=0.07445553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAPLN2	NM_021817.3	c.16A>G	p.Thr6Ala	missense_variant	3/7	ENST00000255039.6
HAPLN2	XM_011509853.3	c.16A>G	p.Thr6Ala	missense_variant	3/7
HAPLN2	XM_017002020.2	c.16A>G	p.Thr6Ala	missense_variant	4/8
HAPLN2	XM_047427123.1	c.258A>G	p.Ser86=	synonymous_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAPLN2	ENST00000255039.6	c.16A>G	p.Thr6Ala	missense_variant	3/7	1	NM_021817.3	P1
HAPLN2	ENST00000456112.1	c.16A>G	p.Thr6Ala	missense_variant	3/5	5
HAPLN2	ENST00000482204.1	n.271A>G		non_coding_transcript_exon_variant	3/3	2
HAPLN2	ENST00000487988.5	n.435A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jan 07, 2022

The c.16A>G (p.T6A) alteration is located in exon 3 (coding exon 1) of the HAPLN2 gene. This alteration results from a A to G substitution at nucleotide position 16, causing the threonine (T) at amino acid position 6 to be replaced by an alanine (A). 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	0.063
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.24
DANN	Benign	0.41
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.29	T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.070	N;N
REVEL	Benign	0.023
Sift	Benign	0.34	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0	B;.
Vest4		0.053
MutPred		0.60		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.25
MPC		0.77
ClinPred		0.057	T
GERP RS		-1.3
Varity_R		0.033
gMVP		0.22

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: rs1571420442; hg19: chr1-156593298;