rs118135975

Variant names:

• chr1-40307503-G-C
• rs118135975
• NM_001852.4:c.955-4C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-40307503-G-C
• chr1-40307503-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001852.4(COL9A2):​c.955-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,613,626 control chromosomes in the GnomAD database, including 466 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (45 hom., cov: 32)
  • Exomes 𝑓: 0.021 (421 hom.)
• Consequence: COL9A2 NM_001852.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004741
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.131
• Publications: 4 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=-0.62).
• BP6: Variant 1-40307503-G-C is Benign according to our data. Variant chr1-40307503-G-C is described in ClinVar as Benign. ClinVar VariationId is 258397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0176 (2677/152320) while in subpopulation SAS AF = 0.033 (159/4822). AF 95% confidence interval is 0.0288. There are 45 homozygotes in GnomAd4. There are 1380 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR,AD gene

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.955-4C>G		splice_region 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.955-4C>G		splice_region intron	N/A	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.1258-4C>G		splice_region intron	N/A
	COL9A2	ENST00000869268.1		c.955-4C>G		splice_region intron	N/A	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2677 AN: 152204 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0271 AC: 6808 AN: 251116 AF XY: 0.0266

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.0530

Gnomad ASJ exome AF: 0.0413

Gnomad EAS exome AF: 0.0223

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0209 AC: 30498 AN: 1461306 Hom.: 421 Cov.: 33 AF XY: 0.0216 AC XY: 15666 AN XY: 726946

African (AFR) AF: 0.00314 AC: 105 AN: 33478

American (AMR) AF: 0.0489 AC: 2185 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0410 AC: 1070 AN: 26126

East Asian (EAS) AF: 0.0329 AC: 1304 AN: 39694

South Asian (SAS) AF: 0.0349 AC: 3009 AN: 86222

European-Finnish (FIN) AF: 0.0250 AC: 1337 AN: 53410

Middle Eastern (MID) AF: 0.0149 AC: 86 AN: 5768

European-Non Finnish (NFE) AF: 0.0182 AC: 20183 AN: 1111540

Other (OTH) AF: 0.0202 AC: 1219 AN: 60380

GnomAD4 genome AF: 0.0176 AC: 2677 AN: 152320 Hom.: 45 Cov.: 32 AF XY: 0.0185 AC XY: 1380 AN XY: 74464

African (AFR) AF: 0.00332 AC: 138 AN: 41560

American (AMR) AF: 0.0250 AC: 382 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 141 AN: 3472

East Asian (EAS) AF: 0.0257 AC: 133 AN: 5182

South Asian (SAS) AF: 0.0330 AC: 159 AN: 4822

European-Finnish (FIN) AF: 0.0230 AC: 244 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1440 AN: 68034

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.0238 Hom.: 13

Bravo AF: 0.0166

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.0198

EpiControl AF: 0.0161

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Connective tissue disorder (1)
-	-	1	Epiphyseal dysplasia, multiple, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.3
DANN	Benign	0.65
PhyloP100		-0.13
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0060
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: rs118135975; hg19: chr1-40773175; COSMIC: COSV65607253; COSMIC: COSV65607253;