chr6-70234582-C-T

Variant names:

• chr6-70234582-C-T
• rs2072650
• NM_001851.6:c.2271G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001851.6(COL9A1):​c.2271G>A​(p.Pro757Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,614,076 control chromosomes in the GnomAD database, including 804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P757P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (78 hom., cov: 32)
  • Exomes 𝑓: 0.019 (726 hom.)
• Consequence: COL9A1 NM_001851.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.39
• Publications: 15 publications found

Genes affected

COL9A1 (HGNC:2217): (collagen type IX alpha 1 chain) This gene encodes one of the three alpha chains of type IX collagen, which is a minor (5-20%) collagen component of hyaline cartilage. Type IX collagen is usually found in tissues containing type II collagen, a fibrillar collagen. Studies in knockout mice have shown that synthesis of the alpha 1 chain is essential for assembly of type IX collagen molecules, a heterotrimeric molecule, and that lack of type IX collagen is associated with early onset osteoarthritis. Mutations in this gene are associated with osteoarthritis in humans, with multiple epiphyseal dysplasia, 6, a form of chondrodysplasia, and with Stickler syndrome, a disease characterized by ophthalmic, orofacial, articular, and auditory defects. Two transcript variants that encode different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

COL9A1 Gene-Disease associations (from GenCC):

• Stickler syndrome, type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• epiphyseal dysplasia, multiple, 6

  Inheritance: Unknown, AR, AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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

ENSG00000253809 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-70234582-C-T is Benign according to our data. Variant chr6-70234582-C-T is described in ClinVar as Benign. ClinVar VariationId is 166949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001851.6. 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
	COL9A1	NM_001851.6	MANE Select	c.2271G>A	p.Pro757Pro	synonymous	Exon 35 of 38	NP_001842.3
	COL9A1	NM_001377289.1		c.1572G>A	p.Pro524Pro	synonymous	Exon 30 of 33	NP_001364218.1	A0A804HIB6
	COL9A1	NM_078485.4		c.1542G>A	p.Pro514Pro	synonymous	Exon 29 of 32	NP_511040.2	P20849-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.2271G>A	p.Pro757Pro	synonymous	Exon 35 of 38	ENSP00000349790.6	P20849-1
	COL9A1	ENST00000320755.12	TSL:1	c.1542G>A	p.Pro514Pro	synonymous	Exon 29 of 32	ENSP00000315252.7	P20849-2
	COL9A1	ENST00000683980.2		c.1572G>A	p.Pro524Pro	synonymous	Exon 30 of 33	ENSP00000506990.1	A0A804HIB6

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2280 AN: 152156 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00550

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.0613

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0253 AC: 6371 AN: 251370 AF XY: 0.0275

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.00853

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0188 AC: 27523 AN: 1461802 Hom.: 726 Cov.: 32 AF XY: 0.0202 AC XY: 14717 AN XY: 727194

African (AFR) AF: 0.00559 AC: 187 AN: 33480

American (AMR) AF: 0.00841 AC: 376 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00597 AC: 156 AN: 26136

East Asian (EAS) AF: 0.133 AC: 5295 AN: 39692

South Asian (SAS) AF: 0.0665 AC: 5734 AN: 86248

European-Finnish (FIN) AF: 0.00249 AC: 133 AN: 53416

Middle Eastern (MID) AF: 0.0303 AC: 175 AN: 5768

European-Non Finnish (NFE) AF: 0.0127 AC: 14127 AN: 1111946

Other (OTH) AF: 0.0222 AC: 1340 AN: 60392

GnomAD4 genome AF: 0.0150 AC: 2286 AN: 152274 Hom.: 78 Cov.: 32 AF XY: 0.0165 AC XY: 1229 AN XY: 74452

African (AFR) AF: 0.00551 AC: 229 AN: 41544

American (AMR) AF: 0.0105 AC: 161 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.132 AC: 684 AN: 5190

South Asian (SAS) AF: 0.0620 AC: 299 AN: 4824

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0121 AC: 826 AN: 68024

Other (OTH) AF: 0.0176 AC: 37 AN: 2108

Alfa AF: 0.0122 Hom.: 29

Bravo AF: 0.0144

Asia WGS AF: 0.109 AC: 379 AN: 3478

EpiCase AF: 0.0132

EpiControl AF: 0.0129

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Connective tissue disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.1
DANN	Benign	0.50
PhyloP100		-1.4
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: rs2072650; hg19: chr6-70944285; COSMIC: COSV57885633; COSMIC: COSV57885633;