rs12077871

Variant names:

• chr1-40307478-G-A
• rs12077871
• NM_001852.4:c.976C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-40307478-G-A
• chr1-40307478-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_001852.4(COL9A2):​c.976C>T​(p.Gln326*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,614,022 control chromosomes in the GnomAD database, including 939 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.040 (276 hom., cov: 32)
  • Exomes 𝑓: 0.011 (663 hom.)
• Consequence: COL9A2 NM_001852.4 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.07
• Publications: 28 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 -8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 1-40307478-G-A is Benign according to our data. Variant chr1-40307478-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.976C>T	p.Gln326*	stop_gained	Exon 19 of 32	ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8	c.976C>T	p.Gln326*	stop_gained	Exon 19 of 32	1	NM_001852.4	ENSP00000361834.3
COL9A2	ENST00000482722.5	n.1279C>T		non_coding_transcript_exon_variant	Exon 18 of 31	1

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6075 AN: 152158 Hom.: 277 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0368

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.0363

GnomAD2 exomes AF: 0.0312 AC: 7822 AN: 250928 AF XY: 0.0273

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0698

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.00216

Gnomad OTH exome AF: 0.0188

GnomAD4 exome AF: 0.0115 AC: 16809 AN: 1461746 Hom.: 663 Cov.: 33 AF XY: 0.0115 AC XY: 8352 AN XY: 727166

African (AFR) AF: 0.110 AC: 3677 AN: 33454

American (AMR) AF: 0.0652 AC: 2913 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26136

East Asian (EAS) AF: 0.116 AC: 4599 AN: 39694

South Asian (SAS) AF: 0.0314 AC: 2705 AN: 86238

European-Finnish (FIN) AF: 0.0123 AC: 658 AN: 53416

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5768

European-Non Finnish (NFE) AF: 0.000939 AC: 1044 AN: 1111972

Other (OTH) AF: 0.0186 AC: 1122 AN: 60386

GnomAD4 genome AF: 0.0400 AC: 6085 AN: 152276 Hom.: 276 Cov.: 32 AF XY: 0.0399 AC XY: 2969 AN XY: 74466

African (AFR) AF: 0.105 AC: 4368 AN: 41528

American (AMR) AF: 0.0445 AC: 681 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.109 AC: 561 AN: 5170

South Asian (SAS) AF: 0.0369 AC: 178 AN: 4830

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68036

Other (OTH) AF: 0.0364 AC: 77 AN: 2114

Alfa AF: 0.0160 Hom.: 411

Bravo AF: 0.0465

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0906 AC: 399

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0317 AC: 3849

Asia WGS AF: 0.0610 AC: 215 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Dec 13, 2016

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Epiphyseal dysplasia, multiple, 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		2.1
Vest4		0.74
GERP RS		3.9
Mutation Taster		=139/61	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: rs12077871; hg19: chr1-40773150; COSMIC: COSV101025598; COSMIC: COSV101025598;