rs3737821

Variant names:

• chr1-40302672-C-T
• rs3737821
• NM_001852.4:c.1741G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-40302672-C-T
• chr1-40302672-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001852.4(COL9A2):​c.1741G>A​(p.Val581Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 1,600,116 control chromosomes in the GnomAD database, including 1,677 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (613 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1064 hom.)
• Consequence: COL9A2 NM_001852.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.05
• Publications: 14 publications found

Genes affected

COL9A2 (HGNC:2218): (collagen type IX alpha 2 chain) This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. This chain is unusual in that, unlike the other two type IX alpha chains, it contains a covalently attached glycosaminoglycan side chain. Mutations in this gene are associated with multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

COL9A2 Gene-Disease associations (from GenCC):

• epiphyseal dysplasia, multiple, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome, type 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• multiple epiphyseal dysplasia due to collagen 9 anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Stickler syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013181865).
• BP6: Variant 1-40302672-C-T is Benign according to our data. Variant chr1-40302672-C-T is described in ClinVar as Benign. ClinVar VariationId is 196620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001852.4. 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
	COL9A2	NM_001852.4	MANE Select	c.1741G>A	p.Val581Ile	missense	Exon 30 of 32	NP_001843.1	Q14055

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.1741G>A	p.Val581Ile	missense	Exon 30 of 32	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.2044G>A		non_coding_transcript_exon	Exon 29 of 31
	COL9A2	ENST00000869268.1		c.1825G>A	p.Val609Ile	missense	Exon 30 of 32	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9814 AN: 152050 Hom.: 608 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0418

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0380 AC: 8454 AN: 222764 AF XY: 0.0345

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.0590

Gnomad ASJ exome AF: 0.0401

Gnomad EAS exome AF: 0.0218

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.0200

Gnomad OTH exome AF: 0.0275

GnomAD4 exome AF: 0.0257 AC: 37231 AN: 1447948 Hom.: 1064 Cov.: 35 AF XY: 0.0257 AC XY: 18504 AN XY: 719292

African (AFR) AF: 0.180 AC: 5944 AN: 33082

American (AMR) AF: 0.0564 AC: 2446 AN: 43368

Ashkenazi Jewish (ASJ) AF: 0.0408 AC: 1055 AN: 25852

East Asian (EAS) AF: 0.0328 AC: 1277 AN: 38904

South Asian (SAS) AF: 0.0353 AC: 2961 AN: 83926

European-Finnish (FIN) AF: 0.0247 AC: 1268 AN: 51248

Middle Eastern (MID) AF: 0.0236 AC: 115 AN: 4882

European-Non Finnish (NFE) AF: 0.0183 AC: 20242 AN: 1106924

Other (OTH) AF: 0.0322 AC: 1923 AN: 59762

GnomAD4 genome AF: 0.0647 AC: 9849 AN: 152168 Hom.: 613 Cov.: 32 AF XY: 0.0651 AC XY: 4842 AN XY: 74414

African (AFR) AF: 0.168 AC: 6963 AN: 41500

American (AMR) AF: 0.0418 AC: 639 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3472

East Asian (EAS) AF: 0.0260 AC: 134 AN: 5150

South Asian (SAS) AF: 0.0338 AC: 163 AN: 4824

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1461 AN: 67984

Other (OTH) AF: 0.0458 AC: 97 AN: 2116

Alfa AF: 0.0365 Hom.: 1012

Bravo AF: 0.0705

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.153 AC: 670

ESP6500EA AF: 0.0200 AC: 172

ExAC AF: 0.0370 AC: 4465

Asia WGS AF: 0.0640 AC: 223 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Epiphyseal dysplasia, multiple, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.90
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.74	N
PhyloP100		1.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	0.59	T
Polyphen		0.48	P
Vest4		0.050
MPC		0.22
ClinPred		0.0034	T
GERP RS		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.038
gMVP		0.32
Mutation Taster		=99/1	polymorphism (auto)

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: rs3737821; hg19: chr1-40768344;