rs189374343

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBP6

The NM_000089.4(COL1A2):c.2168A>G(p.Asn723Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N723I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

COL1A2
NM_000089.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 3.21

Publications

5 publications found

Variant links:

Genes affected

COL1A2 (HGNC:2198): (collagen type I alpha 2 chain) This gene encodes the pro-alpha2 chain of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

COL1A2 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, arthrochalasia type, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
osteogenesis imperfecta
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
osteogenesis imperfecta type 1
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
osteogenesis imperfecta type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
osteogenesis imperfecta type 3
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
osteogenesis imperfecta type 4
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Ehlers-Danlos syndrome, arthrochalasia type
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
Ehlers-Danlos syndrome, cardiac valvular type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, PanelApp Australia, Orphanet, G2P
combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2
Inheritance: AD Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
Ehlers-Danlos/osteogenesis imperfecta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
high bone mass osteogenesis imperfecta
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL1A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000089.4

PP2

Missense variant in the COL1A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 437 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 2.1491 (below the threshold of 3.09). Trascript score misZ: 3.5344 (above the threshold of 3.09). GenCC associations: The gene is linked to osteogenesis imperfecta, osteogenesis imperfecta type 1, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, cardiac valvular type, Ehlers-Danlos syndrome, arthrochalasia type, 2, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, osteogenesis imperfecta type 2, high bone mass osteogenesis imperfecta, Ehlers-Danlos/osteogenesis imperfecta syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.04555601).

BP6

Variant 7-94420425-A-G is Benign according to our data. Variant chr7-94420425-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360961.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4 link	c.2168A>G	p.Asn723Ser	missense_variant	Exon 36 of 52	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11 link	c.2168A>G	p.Asn723Ser	missense_variant	Exon 36 of 52	1	NM_000089.4	ENSP00000297268.6

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000967

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000167

AC:

AN:

251418

AF XY:

0.000169

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.000492

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000957

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000701

AC:

AN:

1111996

Other (OTH)

AF:

0.000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000270

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41490

American (AMR)

AF:

0.00124

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000969

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67972

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000243

Hom.:

Bravo

AF:

0.000295

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL1A2 c.2168A>G; p.Asn723Ser variant (rs189374343), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 360961). This variant is found in the general population with an overall allele frequency of 0.017% (47/282806 alleles) in the Genome Aggregation Database. The asparagine at codon 723 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.178). Due to limited information, the clinical significance of the p.Asn723Ser variant is uncertain at this time.

Oct 08, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Dec 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL1A2 c.2168A>G (p.Asn723Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 1613980 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL1A2 causing Osteoporosis (0.00013 vs 0.0014), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2168A>G in individuals affected with Osteoporosis and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 360961). Based on the evidence outlined above, the variant was classified as uncertain significance.

Cardiovascular phenotype

Uncertain:1

Dec 31, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.N723S variant (also known as c.2168A>G), located in coding exon 36 of the COL1A2 gene, results from an A to G substitution at nucleotide position 2168. The asparagine at codon 723 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Osteogenesis imperfecta

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Ehlers-Danlos syndrome, arthrochalasia type, 2

Benign:1

Jan 13, 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.

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1

Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Connective tissue disorder

Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

0.0026

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.046

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.62

N;.

PhyloP100

3.2

PrimateAI

Benign

0.47

PROVEAN

Benign

0.69

N;.

REVEL

Benign

0.18

Sift

Benign

0.23

T;.

Sift4G

Benign

0.15

T;T

Vest4

0.22

ClinPred

0.022

GERP RS

5.7

Varity_R

0.030

gMVP

0.26

Mutation Taster

=91/9

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over