1-156624736-G-C

Variant names:

• chr1-156624736-G-C
• rs867961092
• NM_021817.3:c.692G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021817.3(HAPLN2):​c.692G>C​(p.Arg231Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000513 in 1,559,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HAPLN2 NM_021817.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.855
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07692838).

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>C	p.Arg231Pro	missense	Exon 6 of 7	NP_068589.1	Q9GZV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAPLN2	ENST00000255039.6	TSL:1 MANE Select	c.692G>C	p.Arg231Pro	missense	Exon 6 of 7	ENSP00000255039.1	Q9GZV7
	HAPLN2	ENST00000858239.1		c.734G>C	p.Arg245Pro	missense	Exon 6 of 7	ENSP00000528298.1
	HAPLN2	ENST00000968562.1		c.734G>C	p.Arg245Pro	missense	Exon 6 of 7	ENSP00000638621.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1407158 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 697364

African (AFR) AF: 0.0000932 AC: 3 AN: 32186

American (AMR) AF: 0.00 AC: 0 AN: 37308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24316

East Asian (EAS) AF: 0.00 AC: 0 AN: 38024

South Asian (SAS) AF: 0.00 AC: 0 AN: 80104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092832

Other (OTH) AF: 0.00 AC: 0 AN: 58416

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

African (AFR) AF: 0.000121 AC: 5 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	23
DANN	Benign	0.49
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.85
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.10
Sift	Benign	0.082	T
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.27
MutPred		0.48		Loss of MoRF binding (P = 0.0074)
MVP		0.21
MPC		1.1
ClinPred		0.62	D
GERP RS		-1.1
Varity_R		0.40
gMVP		0.90
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs867961092; hg19: chr1-156594528;