rs2622875

Variant names:

• chr1-103002739-C-T
• rs2622875
• NM_001854.4:c.2043+8G>A

Variant summary

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

The NM_001854.4(COL11A1):​c.2043+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,609,480 control chromosomes in the GnomAD database, including 878 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 0.044 (253 hom., cov: 32)
  • Exomes 𝑓: 0.024 (625 hom.)
• Consequence: COL11A1 NM_001854.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002870
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.19
• Publications: 7 publications found

Genes affected

COL11A1 (HGNC:2186): (collagen type XI alpha 1 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Mutations in this gene are associated with type II Stickler syndrome and with Marshall syndrome. A single-nucleotide polymorphism in this gene is also associated with susceptibility to lumbar disc herniation. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

COL11A1 Gene-Disease associations (from GenCC):

• Marshall syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Stickler syndrome type 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, Genomics England PanelApp
• fibrochondrogenesis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal dominant 37

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fibrochondrogenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-103002739-C-T is Benign according to our data. Variant chr1-103002739-C-T is described in ClinVar as Benign. ClinVar VariationId is 258442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.095 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.2043+8G>A		splice_region_variant, intron_variant	Intron 22 of 66	ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.2043+8G>A		splice_region_variant, intron_variant	Intron 22 of 66	1	NM_001854.4	ENSP00000359114.3

Frequencies

GnomAD3 genomes AF: 0.0440 AC: 6696 AN: 152022 Hom.: 251 Cov.: 32

Gnomad AFR AF: 0.0972

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00579

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0466

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0461

GnomAD2 exomes AF: 0.0294 AC: 7378 AN: 251116 AF XY: 0.0274

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.00490

Gnomad FIN exome AF: 0.0432

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0307

GnomAD4 exome AF: 0.0244 AC: 35570 AN: 1457340 Hom.: 625 Cov.: 30 AF XY: 0.0238 AC XY: 17263 AN XY: 725366

African (AFR) AF: 0.104 AC: 3479 AN: 33292

American (AMR) AF: 0.0350 AC: 1565 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 747 AN: 26080

East Asian (EAS) AF: 0.00451 AC: 179 AN: 39656

South Asian (SAS) AF: 0.0188 AC: 1617 AN: 86172

European-Finnish (FIN) AF: 0.0426 AC: 2276 AN: 53410

Middle Eastern (MID) AF: 0.0579 AC: 333 AN: 5748

European-Non Finnish (NFE) AF: 0.0212 AC: 23470 AN: 1108094

Other (OTH) AF: 0.0316 AC: 1904 AN: 60228

GnomAD4 genome AF: 0.0442 AC: 6717 AN: 152140 Hom.: 253 Cov.: 32 AF XY: 0.0448 AC XY: 3331 AN XY: 74360

African (AFR) AF: 0.0975 AC: 4046 AN: 41502

American (AMR) AF: 0.0311 AC: 475 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3470

East Asian (EAS) AF: 0.00580 AC: 30 AN: 5170

South Asian (SAS) AF: 0.0185 AC: 89 AN: 4822

European-Finnish (FIN) AF: 0.0466 AC: 494 AN: 10592

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0202 AC: 1376 AN: 68006

Other (OTH) AF: 0.0451 AC: 95 AN: 2106

Alfa AF: 0.0319 Hom.: 74

Bravo AF: 0.0474

Asia WGS AF: 0.0260 AC: 89 AN: 3478

EpiCase AF: 0.0246

EpiControl AF: 0.0225

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 03, 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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 24, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibrochondrogenesis 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Stickler syndrome type 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Connective tissue disorder Benign:1

Apr 01, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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	-0.74
CADD	Benign	0.93
DANN	Benign	0.57
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.010
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: rs2622875; hg19: chr1-103468295;