1-40303502-G-T

Variant names:

• chr1-40303502-G-T
• rs76810153
• NM_001852.4:c.1548+28C>A

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.1548+28C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,612,116 control chromosomes in the GnomAD database, including 1,959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (750 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1209 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.41
• 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=-0.95).
• BP6: Variant 1-40303502-G-T is Benign according to our data. Variant chr1-40303502-G-T is described in ClinVar as Benign. ClinVar VariationId is 258376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.1548+28C>A		intron_variant	Intron 28 of 31	ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8	c.1548+28C>A		intron_variant	Intron 28 of 31	1	NM_001852.4	ENSP00000361834.3
COL9A2	ENST00000482722.5	n.1851+28C>A		intron_variant	Intron 27 of 30	1
COL9A2	ENST00000427563.1	n.359+28C>A		intron_variant	Intron 6 of 6	3
COL9A2	ENST00000466267.1	n.513+28C>A		intron_variant	Intron 8 of 10	5

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 10639 AN: 152074 Hom.: 743 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0447

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.0338

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0468

GnomAD2 exomes AF: 0.0387 AC: 9468 AN: 244612 AF XY: 0.0350

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.0605

Gnomad ASJ exome AF: 0.0403

Gnomad EAS exome AF: 0.0218

Gnomad FIN exome AF: 0.0229

Gnomad NFE exome AF: 0.0200

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0262 AC: 38226 AN: 1459924 Hom.: 1209 Cov.: 35 AF XY: 0.0261 AC XY: 18967 AN XY: 726270

African (AFR) AF: 0.197 AC: 6591 AN: 33402

American (AMR) AF: 0.0580 AC: 2584 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 1069 AN: 26114

East Asian (EAS) AF: 0.0327 AC: 1299 AN: 39678

South Asian (SAS) AF: 0.0352 AC: 3038 AN: 86186

European-Finnish (FIN) AF: 0.0249 AC: 1298 AN: 52172

Middle Eastern (MID) AF: 0.0250 AC: 144 AN: 5764

European-Non Finnish (NFE) AF: 0.0181 AC: 20171 AN: 1111678

Other (OTH) AF: 0.0337 AC: 2032 AN: 60348

GnomAD4 genome AF: 0.0702 AC: 10678 AN: 152192 Hom.: 750 Cov.: 32 AF XY: 0.0701 AC XY: 5219 AN XY: 74412

African (AFR) AF: 0.187 AC: 7744 AN: 41504

American (AMR) AF: 0.0446 AC: 682 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 141 AN: 3470

East Asian (EAS) AF: 0.0257 AC: 133 AN: 5174

South Asian (SAS) AF: 0.0336 AC: 162 AN: 4822

European-Finnish (FIN) AF: 0.0230 AC: 244 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0215 AC: 1459 AN: 67994

Other (OTH) AF: 0.0496 AC: 105 AN: 2116

Alfa AF: 0.0520 Hom.: 71

Bravo AF: 0.0767

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.24
DANN	Benign	0.66
PhyloP100		-2.4
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: rs76810153; hg19: chr1-40769174;