rs2301643

Variant names:

• chr7-94414181-G-A
• rs2301643
• NM_000089.4:c.1666-41G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-94414181-G-A
• chr7-94414181-G-C
• chr7-94414181-G-T

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.1666-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,603,114 control chromosomes in the GnomAD database, including 28,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2416 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25882 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.60
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-94414181-G-A is Benign according to our data. Variant chr7-94414181-G-A is described in ClinVar as Benign. ClinVar VariationId is 674830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.1666-41G>A		intron_variant	Intron 28 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.1666-41G>A		intron_variant	Intron 28 of 51	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000488298.5	n.90-41G>A		intron_variant	Intron 2 of 4	2
COL1A2	ENST00000473573.5	n.-39G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26069 AN: 151968 Hom.: 2412 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0854

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.183 AC: 45784 AN: 250562 AF XY: 0.175

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.347

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.0993

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.184 AC: 267454 AN: 1451028 Hom.: 25882 Cov.: 30 AF XY: 0.181 AC XY: 130814 AN XY: 722608

African (AFR) AF: 0.139 AC: 4631 AN: 33208

American (AMR) AF: 0.341 AC: 15203 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4709 AN: 26046

East Asian (EAS) AF: 0.104 AC: 4133 AN: 39656

South Asian (SAS) AF: 0.108 AC: 9285 AN: 85972

European-Finnish (FIN) AF: 0.107 AC: 5712 AN: 53392

Middle Eastern (MID) AF: 0.143 AC: 825 AN: 5750

European-Non Finnish (NFE) AF: 0.193 AC: 212301 AN: 1102386

Other (OTH) AF: 0.178 AC: 10655 AN: 60024

GnomAD4 genome AF: 0.172 AC: 26091 AN: 152086 Hom.: 2416 Cov.: 32 AF XY: 0.169 AC XY: 12537 AN XY: 74344

African (AFR) AF: 0.141 AC: 5856 AN: 41480

American (AMR) AF: 0.285 AC: 4347 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 567 AN: 3468

East Asian (EAS) AF: 0.115 AC: 595 AN: 5168

South Asian (SAS) AF: 0.108 AC: 519 AN: 4822

European-Finnish (FIN) AF: 0.0854 AC: 904 AN: 10590

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12797 AN: 67968

Other (OTH) AF: 0.185 AC: 391 AN: 2114

Alfa AF: 0.124 Hom.: 259

Bravo AF: 0.187

Asia WGS AF: 0.114 AC: 396 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.5
DANN	Benign	0.63
PhyloP100		1.6
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: rs2301643; hg19: chr7-94043493; COSMIC: COSV51955100; COSMIC: COSV51955100;