rs2072650

Positions:

• chr6-70234582-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001851.6(COL9A1):​c.2271G>A​(p.Pro757=) 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 (★★).

• 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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 166949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-70234582-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.2271G>A	p.Pro757=	synonymous_variant	35/38	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.2271G>A	p.Pro757=	synonymous_variant	35/38	1	NM_001851.6	ENSP00000349790	P1
	ENST00000522264.1	n.82-7402C>T		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.0253 AC: 6371 AN: 251370 Hom.: 245 AF XY: 0.0275 AC XY: 3738 AN XY: 135856

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 SAS exome AF: 0.0679

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

Gnomad4 AFR exome AF: 0.00559

Gnomad4 AMR exome AF: 0.00841

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.0665

Gnomad4 FIN exome AF: 0.00249

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0222

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

Gnomad4 AFR AF: 0.00551

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.0620

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.0128 Hom.: 25

Bravo AF: 0.0144

Asia WGS AF: 0.109 AC: 379 AN: 3478

EpiCase AF: 0.0132

EpiControl AF: 0.0129

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.1
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs2072650; hg19: chr6-70944285; COSMIC: COSV57885633; COSMIC: COSV57885633;