rs77695700

Variant names:

• chr1-40304111-G-A
• rs77695700
• NM_001852.4:c.1288-12C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-40304111-G-A
• chr1-40304111-G-T

Variant summary

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

The NM_001852.4(COL9A2):​c.1288-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0332 in 1,548,576 control chromosomes in the GnomAD database, including 1,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (136 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1287 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Scores: Splicing: ADA: 0.00001605
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.35
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-40304111-G-A is Benign according to our data. Variant chr1-40304111-G-A is described in ClinVar as Benign. ClinVar VariationId is 258370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

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.1288-12C>T		intron	N/A	NP_001843.1	Q14055

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.1288-12C>T		intron	N/A	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.1591-12C>T		intron	N/A
	COL9A2	ENST00000869268.1		c.1372-12C>T		intron	N/A	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4529 AN: 152082 Hom.: 135 Cov.: 32

Gnomad AFR AF: 0.00782

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.0515 AC: 8017 AN: 155602 AF XY: 0.0524

Gnomad AFR exome AF: 0.00696

Gnomad AMR exome AF: 0.0562

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.0296

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0336 AC: 46945 AN: 1396376 Hom.: 1287 Cov.: 33 AF XY: 0.0348 AC XY: 23939 AN XY: 688640

African (AFR) AF: 0.00723 AC: 233 AN: 32220

American (AMR) AF: 0.0531 AC: 1917 AN: 36132

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 439 AN: 24886

East Asian (EAS) AF: 0.146 AC: 5382 AN: 36910

South Asian (SAS) AF: 0.0803 AC: 6395 AN: 79594

European-Finnish (FIN) AF: 0.0256 AC: 1120 AN: 43764

Middle Eastern (MID) AF: 0.0332 AC: 173 AN: 5216

European-Non Finnish (NFE) AF: 0.0271 AC: 29271 AN: 1079728

Other (OTH) AF: 0.0348 AC: 2015 AN: 57926

GnomAD4 genome AF: 0.0298 AC: 4533 AN: 152200 Hom.: 136 Cov.: 32 AF XY: 0.0315 AC XY: 2347 AN XY: 74404

African (AFR) AF: 0.00780 AC: 324 AN: 41534

American (AMR) AF: 0.0382 AC: 585 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.157 AC: 811 AN: 5156

South Asian (SAS) AF: 0.0973 AC: 469 AN: 4822

European-Finnish (FIN) AF: 0.0273 AC: 289 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0274 AC: 1864 AN: 67994

Other (OTH) AF: 0.0266 AC: 56 AN: 2108

Alfa AF: 0.0146 Hom.: 9

Bravo AF: 0.0297

Asia WGS AF: 0.113 AC: 393 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Epiphyseal dysplasia, multiple, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.34
DANN	Benign	0.64
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		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: rs77695700; hg19: chr1-40769783; COSMIC: COSV65622821;