rs3736638

Variant names:

• chr7-94417954-C-A
• rs3736638
• NM_000089.4:c.1971+123C>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.1971+123C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 797,364 control chromosomes in the GnomAD database, including 4,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (1266 hom., cov: 32)
  • Exomes 𝑓: 0.043 (2796 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.132
• 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=-0.84).
• BP6: Variant 7-94417954-C-A is Benign according to our data. Variant chr7-94417954-C-A is described in ClinVar as Benign. ClinVar VariationId is 678062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.1971+123C>A		intron_variant	Intron 32 of 51	ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.1971+123C>A		intron_variant	Intron 32 of 51	1	NM_000089.4	ENSP00000297268.6
COL1A2	ENST00000461525.5	n.60+123C>A		intron_variant	Intron 1 of 6	1
COL1A2	ENST00000473573.5	n.308+123C>A		intron_variant	Intron 4 of 10	2
COL1A2	ENST00000497316.5	n.368+123C>A		intron_variant	Intron 1 of 8	2

Frequencies

GnomAD3 genomes AF: 0.0840 AC: 12759 AN: 151908 Hom.: 1257 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0655

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.0683

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0758

GnomAD4 exome AF: 0.0427 AC: 27569 AN: 645338 Hom.: 2796 AF XY: 0.0416 AC XY: 14256 AN XY: 342792

African (AFR) AF: 0.196 AC: 3355 AN: 17132

American (AMR) AF: 0.0685 AC: 2330 AN: 34038

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 284 AN: 19892

East Asian (EAS) AF: 0.356 AC: 11446 AN: 32124

South Asian (SAS) AF: 0.0536 AC: 3356 AN: 62666

European-Finnish (FIN) AF: 0.0314 AC: 1270 AN: 40420

Middle Eastern (MID) AF: 0.0162 AC: 43 AN: 2652

European-Non Finnish (NFE) AF: 0.00952 AC: 3837 AN: 403144

Other (OTH) AF: 0.0495 AC: 1648 AN: 33270

GnomAD4 genome AF: 0.0842 AC: 12800 AN: 152026 Hom.: 1266 Cov.: 32 AF XY: 0.0853 AC XY: 6339 AN XY: 74320

African (AFR) AF: 0.200 AC: 8289 AN: 41428

American (AMR) AF: 0.0656 AC: 1002 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.374 AC: 1925 AN: 5142

South Asian (SAS) AF: 0.0680 AC: 326 AN: 4796

European-Finnish (FIN) AF: 0.0323 AC: 343 AN: 10616

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 692 AN: 67980

Other (OTH) AF: 0.0802 AC: 169 AN: 2106

Alfa AF: 0.0362 Hom.: 1591

Bravo AF: 0.0934

Asia WGS AF: 0.238 AC: 828 AN: 3478

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	-0.84
CADD	Benign	1.5
DANN	Benign	0.51
PhyloP100		-0.13
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: rs3736638; hg19: chr7-94047266; COSMIC: COSV51969149; COSMIC: COSV51969149;