1-156625131-C-G

Variant names:

• chr1-156625131-C-G
• NM_021817.3:c.770C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021817.3(HAPLN2):​c.770C>G​(p.Thr257Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HAPLN2 NM_021817.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.606

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35397404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAPLN2	NM_021817.3	c.770C>G	p.Thr257Arg	missense_variant	Exon 7 of 7	ENST00000255039.6	NP_068589.1
HAPLN2	XM_011509853.3	c.770C>G	p.Thr257Arg	missense_variant	Exon 7 of 7		XP_011508155.1
HAPLN2	XM_017002020.2	c.770C>G	p.Thr257Arg	missense_variant	Exon 8 of 8		XP_016857509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAPLN2	ENST00000255039.6	c.770C>G	p.Thr257Arg	missense_variant	Exon 7 of 7	1	NM_021817.3	ENSP00000255039.1
HAPLN2	ENST00000494218.1	n.618C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.770C>G (p.T257R) alteration is located in exon 7 (coding exon 5) of the HAPLN2 gene. This alteration results from a C to G substitution at nucleotide position 770, causing the threonine (T) at amino acid position 257 to be replaced by an arginine (R). 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	0.25
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.0016
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.16	B
Vest4		0.39
MutPred		0.68		Gain of methylation at T257 (P = 0.0171);
MVP		0.65
MPC		1.5
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.52
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr1-156594923;