rs189374343

chr7-94420425-A-Gchr7-94420425-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BP6

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. 15/21 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 3.21

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000089.4
• PP2: Missense variant where missense usually causes diseases, COL1A2
• 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 id is 360961.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4	c.2168A>G	p.Asn723Ser	missense_variant	36/52	ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11	c.2168A>G	p.Asn723Ser	missense_variant	36/52	1	NM_000089.4	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 151986 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 251418 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135882

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 SAS exome AF: 0.0000653

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.: 0 Cov.: 33 AF XY: 0.000122 AC XY: 89 AN XY: 727242

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000957

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000701

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74372

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000969

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000295

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 17, 2021	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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	0.0026
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.62	N;.
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.69	N;.
REVEL	Benign	0.18
Sift	Benign	0.23	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.0	B;.
Vest4		0.22
MVP		0.58
MPC		0.17
ClinPred		0.022	T
GERP RS		5.7
Varity_R		0.030
gMVP		0.26

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

Other links and lift over

dbSNP: rs189374343; hg19: chr7-94049737; COSMIC: COSV51960967; COSMIC: COSV51960967;