NM_000089.4:c.1645C>G

Variant names:

• chr7-94413927-C-G
• rs42524
• NM_000089.4:c.1645C>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000089.4(COL1A2):​c.1645C>G​(p.Pro549Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,612,780 control chromosomes in the GnomAD database, including 473,323 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P549S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.80 (49069 hom., cov: 32)
  • Exomes 𝑓: 0.76 (424254 hom.)
• Consequence: COL1A2 NM_000089.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 2.38
• Publications: 106 publications found

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):

• COL1A2-related Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• COL1A2-related osteogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Ehlers-Danlos syndrome, arthrochalasia type, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: Orphanet, Genomics England PanelApp, G2P, ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
• Ehlers-Danlos/osteogenesis imperfecta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• high bone mass osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 13 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 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=9.558573E-6).
• BP6: Variant 7-94413927-C-G is Benign according to our data. Variant chr7-94413927-C-G is described in ClinVar as Benign. ClinVar VariationId is 254953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.894 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000089.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	NM_000089.4	MANE Select	c.1645C>G	p.Pro549Ala	missense	Exon 28 of 52	NP_000080.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	ENST00000297268.11	TSL:1 MANE Select	c.1645C>G	p.Pro549Ala	missense	Exon 28 of 52	ENSP00000297268.6	P08123
	COL1A2	ENST00000959377.1		c.1645C>G	p.Pro549Ala	missense	Exon 28 of 52	ENSP00000629436.1
	COL1A2	ENST00000959379.1		c.1645C>G	p.Pro549Ala	missense	Exon 28 of 52	ENSP00000629438.1

Frequencies

GnomAD3 genomes AF: 0.799 AC: 121542 AN: 152032 Hom.: 49013 Cov.: 32

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.801

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.916

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.759

Gnomad OTH AF: 0.757

GnomAD2 exomes AF: 0.772 AC: 194105 AN: 251322 AF XY: 0.759

Gnomad AFR exome AF: 0.892

Gnomad AMR exome AF: 0.834

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.909

Gnomad FIN exome AF: 0.787

Gnomad NFE exome AF: 0.755

Gnomad OTH exome AF: 0.739

GnomAD4 exome AF: 0.760 AC: 1110177 AN: 1460630 Hom.: 424254 Cov.: 53 AF XY: 0.755 AC XY: 548909 AN XY: 726692

African (AFR) AF: 0.887 AC: 29674 AN: 33462

American (AMR) AF: 0.830 AC: 37120 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 17650 AN: 26126

East Asian (EAS) AF: 0.938 AC: 37253 AN: 39696

South Asian (SAS) AF: 0.644 AC: 55556 AN: 86214

European-Finnish (FIN) AF: 0.783 AC: 41813 AN: 53414

Middle Eastern (MID) AF: 0.611 AC: 3524 AN: 5768

European-Non Finnish (NFE) AF: 0.758 AC: 842393 AN: 1110880

Other (OTH) AF: 0.749 AC: 45194 AN: 60352

GnomAD4 genome AF: 0.800 AC: 121658 AN: 152150 Hom.: 49069 Cov.: 32 AF XY: 0.797 AC XY: 59315 AN XY: 74378

African (AFR) AF: 0.888 AC: 36843 AN: 41496

American (AMR) AF: 0.801 AC: 12244 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2328 AN: 3468

East Asian (EAS) AF: 0.916 AC: 4740 AN: 5174

South Asian (SAS) AF: 0.659 AC: 3179 AN: 4824

European-Finnish (FIN) AF: 0.782 AC: 8277 AN: 10578

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.759 AC: 51612 AN: 68006

Other (OTH) AF: 0.759 AC: 1601 AN: 2110

Alfa AF: 0.753 Hom.: 29772

Bravo AF: 0.809

TwinsUK AF: 0.754 AC: 2795

ALSPAC AF: 0.759 AC: 2925

ESP6500AA AF: 0.883 AC: 3891

ESP6500EA AF: 0.749 AC: 6440

ExAC AF: 0.769 AC: 93397

EpiCase AF: 0.742

EpiControl AF: 0.744

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Ehlers-Danlos syndrome, arthrochalasia type, 2 (2)
-	-	2	not provided (2)
-	-	2	Osteogenesis imperfecta (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, classic type (1)
-	-	1	Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Osteogenesis imperfecta type III (1)
-	-	1	Osteogenesis imperfecta with normal sclerae, dominant form (1)
-	-	1	Osteogenesis imperfecta, perinatal lethal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.030
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.36
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000096	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.29
Sift	Benign	0.98	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.099
MPC		0.20
ClinPred		0.0073	T
GERP RS		5.7
Varity_R		0.025
gMVP		0.36
Mutation Taster		=94/6	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: rs42524; hg19: chr7-94043239; COSMIC: COSV51958215; COSMIC: COSV51958215;