rs28754326

chr7-94409654-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000089.4(COL1A2):c.936+46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,546 control chromosomes in the GnomAD database, including 11,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2022 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9489 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.656

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-94409654-G-A is Benign according to our data. Variant chr7-94409654-G-A is described in ClinVar as [Benign]. Clinvar id is 674979.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4	c.936+46G>A		intron_variant		ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11	c.936+46G>A		intron_variant		1	NM_000089.4	P1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22328 AN: 152048 Hom.: 2015 Cov.: 33

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0426

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0776

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.101 AC: 25408 AN: 251450 Hom.: 1687 AF XY: 0.0967 AC XY: 13138 AN XY: 135900

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.0807

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.0362

Gnomad SAS exome AF: 0.0310

Gnomad FIN exome AF: 0.0803

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.109 AC: 159563 AN: 1461380 Hom.: 9489 Cov.: 41 AF XY: 0.106 AC XY: 77412 AN XY: 727020

Gnomad4 AFR exome AF: 0.260

Gnomad4 AMR exome AF: 0.0859

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.0783

Gnomad4 SAS exome AF: 0.0321

Gnomad4 FIN exome AF: 0.0832

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.147 AC: 22358 AN: 152166 Hom.: 2022 Cov.: 33 AF XY: 0.141 AC XY: 10520 AN XY: 74390

Gnomad4 AFR AF: 0.259

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.0427

Gnomad4 SAS AF: 0.0299

Gnomad4 FIN AF: 0.0776

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.142

Alfa AF: 0.131 Hom.: 298

Bravo AF: 0.157

Asia WGS AF: 0.0520 AC: 181 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.2
Dann	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs28754326; hg19: chr7-94038966;