rs6465412

Variant names:

• chr7-94429083-T-C
• rs6465412
• NM_000089.4:c.3712-105T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-94429083-T-C
• chr7-94429083-T-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.3712-105T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 882,434 control chromosomes in the GnomAD database, including 52,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (18182 hom., cov: 28)
  • Exomes 𝑓: 0.27 (34291 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0790
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-94429083-T-C is Benign according to our data. Variant chr7-94429083-T-C is described in ClinVar as Benign. ClinVar VariationId is 674980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.3712-105T>C		intron_variant	Intron 50 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.3712-105T>C		intron_variant	Intron 50 of 51	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000464916.1	n.760-105T>C		intron_variant	Intron 2 of 3	2
COL1A2	ENST00000481570.5	n.4493-105T>C		intron_variant	Intron 7 of 7	2

Frequencies

GnomAD3 genomes AF: 0.432 AC: 64329 AN: 148958 Hom.: 18133 Cov.: 28

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.390

GnomAD4 exome AF: 0.266 AC: 194831 AN: 733390 Hom.: 34291 AF XY: 0.262 AC XY: 99411 AN XY: 379944

African (AFR) AF: 0.808 AC: 12181 AN: 15070

American (AMR) AF: 0.242 AC: 5417 AN: 22416

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 3680 AN: 17114

East Asian (EAS) AF: 0.583 AC: 18660 AN: 31990

South Asian (SAS) AF: 0.200 AC: 10677 AN: 53518

European-Finnish (FIN) AF: 0.303 AC: 11048 AN: 36484

Middle Eastern (MID) AF: 0.229 AC: 716 AN: 3124

European-Non Finnish (NFE) AF: 0.236 AC: 122405 AN: 518774

Other (OTH) AF: 0.288 AC: 10047 AN: 34900

GnomAD4 genome AF: 0.432 AC: 64423 AN: 149044 Hom.: 18182 Cov.: 28 AF XY: 0.426 AC XY: 30957 AN XY: 72614

African (AFR) AF: 0.807 AC: 32405 AN: 40170

American (AMR) AF: 0.297 AC: 4481 AN: 15078

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 906 AN: 3456

East Asian (EAS) AF: 0.554 AC: 2790 AN: 5038

South Asian (SAS) AF: 0.241 AC: 1143 AN: 4740

European-Finnish (FIN) AF: 0.317 AC: 3102 AN: 9794

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.273 AC: 18460 AN: 67512

Other (OTH) AF: 0.395 AC: 817 AN: 2066

Alfa AF: 0.313 Hom.: 12949

Bravo AF: 0.454

Asia WGS AF: 0.435 AC: 1489 AN: 3420

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 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	-0.88
CADD	Benign	3.0
DANN	Benign	0.47
PhyloP100		-0.079
Mutation Taster		=100/0	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: rs6465412; hg19: chr7-94058395;