rs3736638

Positions:

• chr7-94417954-C-A

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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/exons	MANE	Protein	UniProt
COL1A2	NM_000089.4	c.1971+123C>A		intron_variant		ENST00000297268.11	NP_000080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11	c.1971+123C>A		intron_variant		1	NM_000089.4	ENSP00000297268	P1
COL1A2	ENST00000461525.5	n.60+123C>A		intron_variant, non_coding_transcript_variant		1
COL1A2	ENST00000473573.5	n.308+123C>A		intron_variant, non_coding_transcript_variant		2
COL1A2	ENST00000497316.5	n.368+123C>A		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR exome AF: 0.196

Gnomad4 AMR exome AF: 0.0685

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.0536

Gnomad4 FIN exome AF: 0.0314

Gnomad4 NFE exome AF: 0.00952

Gnomad4 OTH exome AF: 0.0495

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

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.0656

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.374

Gnomad4 SAS AF: 0.0680

Gnomad4 FIN AF: 0.0323

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.0802

Alfa AF: 0.0286 Hom.: 465

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

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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.51

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: rs3736638; hg19: chr7-94047266; COSMIC: COSV51969149; COSMIC: COSV51969149;