rs74335369

Variant names:

• chr7-94429175-C-T
• rs74335369
• NM_000089.4:c.3712-13C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-94429175-C-T
• chr7-94429175-C-A
• chr7-94429175-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.3712-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,603,358 control chromosomes in the GnomAD database, including 426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (214 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (212 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0750
• Publications: 2 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

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, ClinGen
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, cardiac valvular type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, 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=-0.82).
• BP6: Variant 7-94429175-C-T is Benign according to our data. Variant chr7-94429175-C-T is described in ClinVar as Benign. ClinVar VariationId is 360971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0968 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.3712-13C>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.3712-13C>T		intron	N/A	ENSP00000297268.6	P08123
	COL1A2	ENST00000959377.1		c.3709-13C>T		intron	N/A	ENSP00000629436.1
	COL1A2	ENST00000959379.1		c.3709-13C>T		intron	N/A	ENSP00000629438.1

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4259 AN: 149488 Hom.: 213 Cov.: 31

Gnomad AFR AF: 0.0996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00928

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00923

Gnomad SAS AF: 0.000631

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.0209

GnomAD2 exomes AF: 0.00825 AC: 2061 AN: 249728 AF XY: 0.00614

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00972

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00327 AC: 4752 AN: 1453768 Hom.: 212 Cov.: 32 AF XY: 0.00285 AC XY: 2059 AN XY: 723438

African (AFR) AF: 0.107 AC: 3525 AN: 33088

American (AMR) AF: 0.00487 AC: 217 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 25984

East Asian (EAS) AF: 0.00957 AC: 377 AN: 39390

South Asian (SAS) AF: 0.000163 AC: 14 AN: 85884

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53222

Middle Eastern (MID) AF: 0.00296 AC: 17 AN: 5738

European-Non Finnish (NFE) AF: 0.000184 AC: 203 AN: 1105896

Other (OTH) AF: 0.00653 AC: 392 AN: 60008

GnomAD4 genome AF: 0.0285 AC: 4261 AN: 149590 Hom.: 214 Cov.: 31 AF XY: 0.0269 AC XY: 1962 AN XY: 72868

African (AFR) AF: 0.0994 AC: 4003 AN: 40268

American (AMR) AF: 0.00927 AC: 139 AN: 15000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00926 AC: 47 AN: 5078

South Asian (SAS) AF: 0.000421 AC: 2 AN: 4746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10030

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000354 AC: 24 AN: 67734

Other (OTH) AF: 0.0207 AC: 43 AN: 2076

Alfa AF: 0.0164 Hom.: 49

Bravo AF: 0.0330

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ehlers-Danlos syndrome, arthrochalasia type, 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Osteogenesis imperfecta (1)
-	-	1	Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.9
DANN	Benign	0.55
PhyloP100		0.075
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs74335369;

hg19: chr7-94058487;

COSMIC: COSV107384998;

COSMIC: COSV107384998;