6-70252336-C-T

Variant names:

• chr6-70252336-C-T
• rs2274584
• NM_001851.6:c.1765-21G>A

Variant summary

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

The NM_001851.6(COL9A1):​c.1765-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,609,078 control chromosomes in the GnomAD database, including 30,551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2581 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27970 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0310
• Publications: 11 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):

• epiphyseal dysplasia, multiple, 6

  Inheritance: AD, AR, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Stickler syndrome, type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.82).
• BP6: Variant 6-70252336-C-T is Benign according to our data. Variant chr6-70252336-C-T is described in ClinVar as Benign. ClinVar VariationId is 258351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.1765-21G>A		intron_variant	Intron 26 of 37	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.1765-21G>A		intron_variant	Intron 26 of 37	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27817 AN: 152054 Hom.: 2578 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.182 AC: 45541 AN: 250830 AF XY: 0.187

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.0938

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.176

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.193 AC: 280824 AN: 1456906 Hom.: 27970 Cov.: 33 AF XY: 0.194 AC XY: 140620 AN XY: 725030

African (AFR) AF: 0.183 AC: 6117 AN: 33378

American (AMR) AF: 0.0979 AC: 4374 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5093 AN: 26100

East Asian (EAS) AF: 0.175 AC: 6940 AN: 39672

South Asian (SAS) AF: 0.217 AC: 18679 AN: 86142

European-Finnish (FIN) AF: 0.200 AC: 10698 AN: 53402

Middle Eastern (MID) AF: 0.215 AC: 1234 AN: 5752

European-Non Finnish (NFE) AF: 0.195 AC: 216007 AN: 1107520

Other (OTH) AF: 0.194 AC: 11682 AN: 60244

GnomAD4 genome AF: 0.183 AC: 27834 AN: 152172 Hom.: 2581 Cov.: 32 AF XY: 0.181 AC XY: 13493 AN XY: 74386

African (AFR) AF: 0.181 AC: 7514 AN: 41544

American (AMR) AF: 0.123 AC: 1883 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 632 AN: 3470

East Asian (EAS) AF: 0.172 AC: 892 AN: 5178

South Asian (SAS) AF: 0.204 AC: 985 AN: 4818

European-Finnish (FIN) AF: 0.200 AC: 2120 AN: 10580

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13154 AN: 67968

Other (OTH) AF: 0.180 AC: 381 AN: 2116

Alfa AF: 0.184 Hom.: 7018

Bravo AF: 0.179

Asia WGS AF: 0.192 AC: 666 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epiphyseal dysplasia, multiple, 6 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.52
PhyloP100		-0.031
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: rs2274584; hg19: chr6-70962039; COSMIC: COSV57889969;