chr1-40304753-G-A

Variant names:

• chr1-40304753-G-A
• rs72944910
• NM_001852.4:c.1161+41C>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.1161+41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0654 in 1,526,022 control chromosomes in the GnomAD database, including 5,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1267 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3763 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.856
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-40304753-G-A is Benign according to our data. Variant chr1-40304753-G-A is described in ClinVar as Benign. ClinVar VariationId is 258368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 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.1161+41C>T		intron	N/A	NP_001843.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.1161+41C>T		intron	N/A	ENSP00000361834.3
	COL9A2	ENST00000482722.5	TSL:1	n.1464+41C>T		intron	N/A
	COL9A2	ENST00000869268.1		c.1202C>T	p.Ala401Val	missense	Exon 22 of 32	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16284 AN: 152132 Hom.: 1254 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.0594

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.0783

GnomAD2 exomes AF: 0.0920 AC: 14081 AN: 153012 AF XY: 0.0895

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.0577

Gnomad EAS exome AF: 0.198

Gnomad FIN exome AF: 0.0523

Gnomad NFE exome AF: 0.0489

Gnomad OTH exome AF: 0.0689

GnomAD4 exome AF: 0.0608 AC: 83502 AN: 1373772 Hom.: 3763 Cov.: 28 AF XY: 0.0618 AC XY: 41921 AN XY: 678156

African (AFR) AF: 0.232 AC: 7204 AN: 31106

American (AMR) AF: 0.111 AC: 3931 AN: 35418

Ashkenazi Jewish (ASJ) AF: 0.0587 AC: 1453 AN: 24762

East Asian (EAS) AF: 0.179 AC: 6355 AN: 35574

South Asian (SAS) AF: 0.116 AC: 9102 AN: 78466

European-Finnish (FIN) AF: 0.0506 AC: 2422 AN: 47866

Middle Eastern (MID) AF: 0.0622 AC: 326 AN: 5240

European-Non Finnish (NFE) AF: 0.0459 AC: 48615 AN: 1058294

Other (OTH) AF: 0.0718 AC: 4094 AN: 57046

GnomAD4 genome AF: 0.107 AC: 16335 AN: 152250 Hom.: 1267 Cov.: 33 AF XY: 0.109 AC XY: 8130 AN XY: 74448

African (AFR) AF: 0.218 AC: 9067 AN: 41546

American (AMR) AF: 0.0868 AC: 1327 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0594 AC: 206 AN: 3470

East Asian (EAS) AF: 0.183 AC: 941 AN: 5156

South Asian (SAS) AF: 0.133 AC: 640 AN: 4824

European-Finnish (FIN) AF: 0.0503 AC: 534 AN: 10618

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0495 AC: 3367 AN: 68022

Other (OTH) AF: 0.0818 AC: 173 AN: 2116

Alfa AF: 0.0447 Hom.: 47

Bravo AF: 0.114

Asia WGS AF: 0.181 AC: 630 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.6
DANN	Benign	0.44
PhyloP100		0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs72944910; hg19: chr1-40770425; COSMIC: COSV65622826; COSMIC: COSV65622826;