NM_001852.4:c.2001C>T

Variant names:

• chr1-40301251-G-A
• rs2229826
• NM_001852.4:c.2001C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001852.4(COL9A2):​c.2001C>T​(p.Ala667Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,132 control chromosomes in the GnomAD database, including 545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (28 hom., cov: 32)
  • Exomes 𝑓: 0.024 (517 hom.)
• Consequence: COL9A2 NM_001852.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.65
• Publications: 1 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-40301251-G-A is Benign according to our data. Variant chr1-40301251-G-A is described in ClinVar as Benign. ClinVar VariationId is 258383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2631/152316) while in subpopulation NFE AF = 0.024 (1635/68032). AF 95% confidence interval is 0.0231. There are 28 homozygotes in GnomAd4. There are 1334 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR,AD gene

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.2001C>T	p.Ala667Ala	synonymous	Exon 32 of 32	NP_001843.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.2001C>T	p.Ala667Ala	synonymous	Exon 32 of 32	ENSP00000361834.3
	COL9A2	ENST00000482722.5	TSL:1	n.2304C>T		non_coding_transcript_exon	Exon 31 of 31
	COL9A2	ENST00000869268.1		c.2085C>T	p.Ala695Ala	synonymous	Exon 32 of 32	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2630 AN: 152198 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0177 AC: 4414 AN: 249702 AF XY: 0.0178

Gnomad AFR exome AF: 0.00466

Gnomad AMR exome AF: 0.00503

Gnomad ASJ exome AF: 0.00826

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0453

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0198

GnomAD4 exome AF: 0.0240 AC: 35049 AN: 1461816 Hom.: 517 Cov.: 31 AF XY: 0.0239 AC XY: 17402 AN XY: 727220

African (AFR) AF: 0.00293 AC: 98 AN: 33480

American (AMR) AF: 0.00561 AC: 251 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00792 AC: 207 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0124 AC: 1068 AN: 86254

European-Finnish (FIN) AF: 0.0462 AC: 2465 AN: 53402

Middle Eastern (MID) AF: 0.0115 AC: 66 AN: 5750

European-Non Finnish (NFE) AF: 0.0267 AC: 29673 AN: 1111982

Other (OTH) AF: 0.0202 AC: 1219 AN: 60390

GnomAD4 genome AF: 0.0173 AC: 2631 AN: 152316 Hom.: 28 Cov.: 32 AF XY: 0.0179 AC XY: 1334 AN XY: 74488

African (AFR) AF: 0.00476 AC: 198 AN: 41576

American (AMR) AF: 0.00856 AC: 131 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4830

European-Finnish (FIN) AF: 0.0513 AC: 545 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1635 AN: 68032

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0201 Hom.: 20

Bravo AF: 0.0135

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0223

EpiControl AF: 0.0222

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Epiphyseal dysplasia, multiple, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.7
DANN	Benign	0.72
PhyloP100		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs2229826; hg19: chr1-40766923;