rs42518

Variant names:

• chr7-94409622-C-T
• rs42518
• NM_000089.4:c.936+14C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-94409622-C-T
• chr7-94409622-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000089.4(COL1A2):​c.936+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 1,613,822 control chromosomes in the GnomAD database, including 490,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50549 hom., cov: 32)
  • Exomes 𝑓: 0.77 (440367 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.993
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-94409622-C-T is Benign according to our data. Variant chr7-94409622-C-T is described in ClinVar as Benign. ClinVar VariationId is 254957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 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.936+14C>T		intron	N/A	NP_000080.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	ENST00000297268.11	TSL:1 MANE Select	c.936+14C>T		intron	N/A	ENSP00000297268.6	P08123
	COL1A2	ENST00000959377.1		c.936+14C>T		intron	N/A	ENSP00000629436.1
	COL1A2	ENST00000959379.1		c.936+14C>T		intron	N/A	ENSP00000629438.1

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123437 AN: 152070 Hom.: 50498 Cov.: 32

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.914

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.775

Gnomad OTH AF: 0.774

GnomAD2 exomes AF: 0.782 AC: 196752 AN: 251478 AF XY: 0.771

Gnomad AFR exome AF: 0.905

Gnomad AMR exome AF: 0.824

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.909

Gnomad FIN exome AF: 0.794

Gnomad NFE exome AF: 0.772

Gnomad OTH exome AF: 0.748

GnomAD4 exome AF: 0.774 AC: 1131898 AN: 1461634 Hom.: 440367 Cov.: 53 AF XY: 0.770 AC XY: 559718 AN XY: 727142

African (AFR) AF: 0.898 AC: 30053 AN: 33480

American (AMR) AF: 0.822 AC: 36746 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 17944 AN: 26134

East Asian (EAS) AF: 0.938 AC: 37255 AN: 39698

South Asian (SAS) AF: 0.660 AC: 56922 AN: 86252

European-Finnish (FIN) AF: 0.789 AC: 42166 AN: 53420

Middle Eastern (MID) AF: 0.638 AC: 3679 AN: 5768

European-Non Finnish (NFE) AF: 0.774 AC: 860962 AN: 1111766

Other (OTH) AF: 0.764 AC: 46171 AN: 60394

GnomAD4 genome AF: 0.812 AC: 123547 AN: 152188 Hom.: 50549 Cov.: 32 AF XY: 0.810 AC XY: 60244 AN XY: 74386

African (AFR) AF: 0.900 AC: 37404 AN: 41540

American (AMR) AF: 0.804 AC: 12301 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2363 AN: 3468

East Asian (EAS) AF: 0.914 AC: 4724 AN: 5166

South Asian (SAS) AF: 0.668 AC: 3217 AN: 4818

European-Finnish (FIN) AF: 0.791 AC: 8388 AN: 10598

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.775 AC: 52661 AN: 67988

Other (OTH) AF: 0.775 AC: 1632 AN: 2106

Alfa AF: 0.774 Hom.: 29248

Bravo AF: 0.821

Asia WGS AF: 0.801 AC: 2786 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Ehlers-Danlos syndrome, arthrochalasia type, 2 (2)
-	-	2	not provided (2)
-	-	1	Osteogenesis imperfecta (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
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.28
DANN	Benign	0.31
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs42518; hg19: chr7-94038934; COSMIC: COSV99800215; COSMIC: COSV99800215;