chr7-94409734-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000089.4(COL1A2):c.948C>T(p.Gly316Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00837 in 1,614,104 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 64 hom. )

Consequence

COL1A2
NM_000089.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.257

Publications

8 publications found

Variant links:

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

COL1A2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000089.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 7-94409734-C-T is Benign according to our data. Variant chr7-94409734-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.257 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00573 (872/152256) while in subpopulation NFE AF = 0.00863 (587/68012). AF 95% confidence interval is 0.00805. There are 5 homozygotes in GnomAd4. There are 447 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR,Unknown gene

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.948C>T	p.Gly316Gly	synonymous	Exon 19 of 52	NP_000080.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL1A2	ENST00000297268.11	TSL:1 MANE Select	c.948C>T	p.Gly316Gly	synonymous	Exon 19 of 52	ENSP00000297268.6	P08123
COL1A2	ENST00000959377.1		c.948C>T	p.Gly316Gly	synonymous	Exon 19 of 52	ENSP00000629436.1
COL1A2	ENST00000959379.1		c.948C>T	p.Gly316Gly	synonymous	Exon 19 of 52	ENSP00000629438.1

Frequencies

GnomAD3 genomes

AF:

0.00573

AC:

871

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00863

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00779

AC:

1958

AN:

251432

AF XY:

0.00845

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00379

Gnomad ASJ exome

AF:

0.0153

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00513

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.00993

GnomAD4 exome

AF:

0.00865

AC:

12644

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00880

AC XY:

6397

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

33478

American (AMR)

AF:

0.00432

AC:

193

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

419

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0107

AC:

925

AN:

86256

European-Finnish (FIN)

AF:

0.00481

AC:

257

AN:

53420

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00915

AC:

10170

AN:

1111978

Other (OTH)

AF:

0.00891

AC:

538

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

764

1527

2291

3054

3818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

388

776

1164

1552

1940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00573

AC:

872

AN:

152256

Hom.:

Cov.:

AF XY:

0.00600

AC XY:

447

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41550

American (AMR)

AF:

0.00366

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00622

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00863

AC:

587

AN:

68012

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00742

Hom.:

Bravo

AF:

0.00555

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0104

EpiControl

AF:

0.00948

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Osteogenesis imperfecta (2)

Cardiovascular phenotype (1)

Ehlers-Danlos syndrome (1)

Ehlers-Danlos syndrome, arthrochalasia type, 2 (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

-0.42

CADD

Benign

5.7

(source)

DANN

Benign

0.65

PhyloP100

0.26

Mutation Taster

=100/0

polymorphism

(source)

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

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over