rs72658163

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM1PP2BP4_ModerateBP6

The NM_000089.4(COL1A2):c.2123G>A(p.Arg708Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,784 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R708P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

COL1A2
NM_000089.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6

Conservation

PhyloP100: 9.01

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000089.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A2. . Gene score misZ 2.1491 (greater than the threshold 3.09). Trascript score misZ 3.5344 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos/osteogenesis imperfecta syndrome, Ehlers-Danlos syndrome, cardiac valvular type, ehlers-danlos syndrome, arthrochalasia type, 2, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, high bone mass osteogenesis imperfecta, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, osteogenesis imperfecta type 4, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.20191616).

BP6

Variant 7-94420276-G-A is Benign according to our data. Variant chr7-94420276-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17250.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4, Benign=1}. Variant chr7-94420276-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4 linkuse as main transcript	c.2123G>A	p.Arg708Gln	missense_variant	35/52	ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11 linkuse as main transcript	c.2123G>A	p.Arg708Gln	missense_variant	35/52	1	NM_000089.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000649

AC:

163

AN:

251232

Hom.:

AF XY:

0.000633

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000925

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00125

AC:

1821

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

888

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00151

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.000743

AC:

113

AN:

152096

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00128

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.000699

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000692

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2021	This variant is associated with the following publications: (PMID: 9923651, 1978725, 15172002, 26432670, 26264438, 27011056, 28017821, 30283886, 30283887, 33195954) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 06, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 01, 2016

- -

Marfan syndrome, atypical

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jun 01, 2004

- -

Postmenopausal osteoporosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 03, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Osteogenesis imperfecta

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Ehlers-danlos syndrome, arthrochalasia type, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.20

T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

0.72

N;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.3

D;.

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;.

Vest4

0.61

MVP

0.88

MPC

0.24

ClinPred

0.060

GERP RS

5.8

Varity_R

0.58

gMVP

0.89

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over