2-189068105-T-C

Variant names:

• chr2-189068105-T-C
• rs2229495
• NM_000393.5:c.1311A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000393.5(COL5A2):​c.1311A>G​(p.Pro437Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.974 in 1,613,694 control chromosomes in the GnomAD database, including 765,725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (69954 hom., cov: 30)
  • Exomes 𝑓: 0.98 (695771 hom.)
• Consequence: COL5A2 NM_000393.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.79
• Publications: 19 publications found

Genes affected

COL5A2 (HGNC:2210): (collagen type V alpha 2 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. [provided by RefSeq, Jul 2008]

COL5A2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-189068105-T-C is Benign according to our data. Variant chr2-189068105-T-C is described in ClinVar as Benign. ClinVar VariationId is 1164099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000393.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.1311A>G	p.Pro437Pro	synonymous	Exon 21 of 54	NP_000384.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.1311A>G	p.Pro437Pro	synonymous	Exon 21 of 54	ENSP00000364000.3
	COL5A2	ENST00000618828.1	TSL:5	c.359-1672A>G		intron	N/A	ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.958 AC: 145710 AN: 152072 Hom.: 69898 Cov.: 30

Gnomad AFR AF: 0.919

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.917

Gnomad ASJ AF: 0.975

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.975

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.982

Gnomad OTH AF: 0.947

GnomAD2 exomes AF: 0.957 AC: 240264 AN: 251160 AF XY: 0.962

Gnomad AFR exome AF: 0.920

Gnomad AMR exome AF: 0.839

Gnomad ASJ exome AF: 0.972

Gnomad EAS exome AF: 0.969

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.982

Gnomad OTH exome AF: 0.961

GnomAD4 exome AF: 0.975 AC: 1425452 AN: 1461504 Hom.: 695771 Cov.: 42 AF XY: 0.976 AC XY: 709629 AN XY: 727086

African (AFR) AF: 0.919 AC: 30762 AN: 33466

American (AMR) AF: 0.846 AC: 37831 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.972 AC: 25403 AN: 26132

East Asian (EAS) AF: 0.938 AC: 37236 AN: 39696

South Asian (SAS) AF: 0.973 AC: 83908 AN: 86244

European-Finnish (FIN) AF: 0.998 AC: 53309 AN: 53420

Middle Eastern (MID) AF: 0.964 AC: 5559 AN: 5764

European-Non Finnish (NFE) AF: 0.983 AC: 1092758 AN: 1111704

Other (OTH) AF: 0.972 AC: 58686 AN: 60384

GnomAD4 genome AF: 0.958 AC: 145824 AN: 152190 Hom.: 69954 Cov.: 30 AF XY: 0.959 AC XY: 71321 AN XY: 74390

African (AFR) AF: 0.919 AC: 38166 AN: 41516

American (AMR) AF: 0.917 AC: 14008 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.975 AC: 3384 AN: 3470

East Asian (EAS) AF: 0.964 AC: 4969 AN: 5152

South Asian (SAS) AF: 0.975 AC: 4700 AN: 4822

European-Finnish (FIN) AF: 0.999 AC: 10594 AN: 10606

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.982 AC: 66798 AN: 68024

Other (OTH) AF: 0.948 AC: 2005 AN: 2116

Alfa AF: 0.968 Hom.: 111801

Bravo AF: 0.947

Asia WGS AF: 0.975 AC: 3391 AN: 3478

EpiCase AF: 0.979

EpiControl AF: 0.977

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.15
DANN	Benign	0.62
PhyloP100		-5.8
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: rs2229495; hg19: chr2-189932831; COSMIC: COSV108216387;