NM_000089.4:c.2078G>A

Variant names:

• chr7-94419550-G-A
• rs34147460
• NM_000089.4:c.2078G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1 PP2 BP4_Strong BP6_Very_Strong BS2

The NM_000089.4(COL1A2):​c.2078G>A​(p.Arg693Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,614,002 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R693W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: COL1A2 NM_000089.4 missense, splice_region
• Scores: Splicing: ADA: 0.9693
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.938
• Publications: 7 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):

• 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• PM1: In a hotspot region, there are 12 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 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=0.012253284).
• BP6: Variant 7-94419550-G-A is Benign according to our data. Variant chr7-94419550-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 392356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	NM_000089.4	MANE Select	c.2078G>A	p.Arg693Gln	missense splice_region	Exon 34 of 52	NP_000080.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	ENST00000297268.11	TSL:1 MANE Select	c.2078G>A	p.Arg693Gln	missense splice_region	Exon 34 of 52	ENSP00000297268.6
	COL1A2	ENST00000461525.5	TSL:1	n.167G>A		splice_region non_coding_transcript_exon	Exon 3 of 7
	COL1A2	ENST00000467931.1	TSL:2	n.98G>A		splice_region non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152074 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00205 AC: 516 AN: 251394 AF XY: 0.00199

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00131 AC: 1910 AN: 1461810 Hom.: 4 Cov.: 31 AF XY: 0.00129 AC XY: 936 AN XY: 727206

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00367 AC: 96 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0106 AC: 564 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00104 AC: 1161 AN: 1111952

Other (OTH) AF: 0.00126 AC: 76 AN: 60390

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152192 Hom.: 1 Cov.: 31 AF XY: 0.00185 AC XY: 138 AN XY: 74406

African (AFR) AF: 0.0000964 AC: 4 AN: 41514

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0111 AC: 118 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68004

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000938 Hom.: 2

Bravo AF: 0.000604

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00201 AC: 244

EpiCase AF: 0.000545

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Osteogenesis imperfecta (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, arthrochalasia type, 2 (1)
-	-	1	Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4303789:Ehlers-Danlos syndrome, cardiac valvular type;C5436847:Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2;CN293783:Ehlers-Danlos syndrome, arthrochalasia type, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.075
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.36	N
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.81	L
PhyloP100		0.94
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.46
Sift	Benign	0.056	T
Sift4G	Benign	0.062	T
Polyphen		0.79	P
Vest4		0.14
MVP		0.78
MPC		0.24
ClinPred		0.024	T
GERP RS		5.5
Varity_R		0.21
gMVP		0.59
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.62
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: rs34147460; hg19: chr7-94048862; COSMIC: COSV99799064; COSMIC: COSV99799064;