rs11764718

Variant names:

• chr7-94430005-G-A
• rs11764718
• NM_000089.4:c.3955-242G>A

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.3955-242G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 549,634 control chromosomes in the GnomAD database, including 15,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3261 hom., cov: 32)
  • Exomes 𝑓: 0.24 (12169 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.441
• Publications: 11 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=-0.9).
• BP6: Variant 7-94430005-G-A is Benign according to our data. Variant chr7-94430005-G-A is described in ClinVar as Benign. ClinVar VariationId is 1248714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.3955-242G>A		intron_variant	Intron 51 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.3955-242G>A		intron_variant	Intron 51 of 51	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000481570.5	n.5310G>A		non_coding_transcript_exon_variant	Exon 8 of 8	2
COL1A2	ENST00000464916.1	n.1003-242G>A		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28665 AN: 152050 Hom.: 3260 Cov.: 32

Gnomad AFR AF: 0.0744

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.225

GnomAD4 exome AF: 0.238 AC: 94645 AN: 397466 Hom.: 12169 Cov.: 4 AF XY: 0.246 AC XY: 52235 AN XY: 211948

African (AFR) AF: 0.0765 AC: 877 AN: 11470

American (AMR) AF: 0.271 AC: 4665 AN: 17226

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 3188 AN: 12204

East Asian (EAS) AF: 0.149 AC: 3976 AN: 26622

South Asian (SAS) AF: 0.362 AC: 15720 AN: 43388

European-Finnish (FIN) AF: 0.141 AC: 3019 AN: 21340

Middle Eastern (MID) AF: 0.309 AC: 537 AN: 1738

European-Non Finnish (NFE) AF: 0.238 AC: 57227 AN: 240384

Other (OTH) AF: 0.235 AC: 5436 AN: 23094

GnomAD4 genome AF: 0.188 AC: 28663 AN: 152168 Hom.: 3261 Cov.: 32 AF XY: 0.187 AC XY: 13898 AN XY: 74394

African (AFR) AF: 0.0743 AC: 3084 AN: 41522

American (AMR) AF: 0.241 AC: 3683 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 886 AN: 3468

East Asian (EAS) AF: 0.182 AC: 941 AN: 5176

South Asian (SAS) AF: 0.368 AC: 1776 AN: 4826

European-Finnish (FIN) AF: 0.125 AC: 1327 AN: 10596

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16247 AN: 67970

Other (OTH) AF: 0.224 AC: 473 AN: 2116

Alfa AF: 0.228 Hom.: 3896

Bravo AF: 0.190

Asia WGS AF: 0.252 AC: 876 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.28
PhyloP100		-0.44
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: rs11764718; hg19: chr7-94059317;