NM_000393.5:c.3689C>G

Variant names:

• chr2-189039508-G-C
• rs62184175
• NM_000393.5:c.3689C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000393.5(COL5A2):​c.3689C>G​(p.Thr1230Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00756 in 1,614,060 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1230A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (59 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.66
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0091317).
• BP6: Variant 2-189039508-G-C is Benign according to our data. Variant chr2-189039508-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00578 (881/152300) while in subpopulation NFE AF = 0.00979 (666/68020). AF 95% confidence interval is 0.00917. There are 5 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 881 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.3689C>G	p.Thr1230Arg	missense	Exon 51 of 54	NP_000384.2	P05997

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.3689C>G	p.Thr1230Arg	missense	Exon 51 of 54	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.3686C>G	p.Thr1229Arg	missense	Exon 51 of 54	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.3581C>G	p.Thr1194Arg	missense	Exon 50 of 53	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.00579 AC: 881 AN: 152182 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00979

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00487 AC: 1221 AN: 250610 AF XY: 0.00509

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.00825

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00774 AC: 11318 AN: 1461760 Hom.: 59 Cov.: 32 AF XY: 0.00751 AC XY: 5463 AN XY: 727182

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00304 AC: 136 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00176 AC: 152 AN: 86242

European-Finnish (FIN) AF: 0.00391 AC: 209 AN: 53386

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5722

European-Non Finnish (NFE) AF: 0.00933 AC: 10379 AN: 1111996

Other (OTH) AF: 0.00599 AC: 362 AN: 60390

GnomAD4 genome AF: 0.00578 AC: 881 AN: 152300 Hom.: 5 Cov.: 31 AF XY: 0.00537 AC XY: 400 AN XY: 74464

African (AFR) AF: 0.00173 AC: 72 AN: 41580

American (AMR) AF: 0.00536 AC: 82 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00979 AC: 666 AN: 68020

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00499 Hom.: 0

Bravo AF: 0.00603

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00456 AC: 554

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00714

EpiControl AF: 0.00705

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Ehlers-Danlos syndrome, classic type, 2 (2)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.53
Sift	Benign	0.33	T
Sift4G	Benign	0.36	T
Polyphen		0.92	P
Vest4		0.60
MVP		0.63
MPC		0.29
ClinPred		0.016	T
GERP RS		5.3
Varity_R		0.16
gMVP		0.77
Mutation Taster		=65/35	polymorphism

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: rs62184175; hg19: chr2-189904234; COSMIC: COSV99058942;