NM_000393.5:c.1081A>C

Variant names:

• chr2-189075416-T-G
• rs76148000
• NM_000393.5:c.1081A>C

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.1081A>C​(p.Met361Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0252 in 1,605,532 control chromosomes in the GnomAD database, including 568 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. M361V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (33 hom., cov: 32)
  • Exomes 𝑓: 0.026 (535 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.45
• Publications: 10 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=0.0057465136).
• BP6: Variant 2-189075416-T-G is Benign according to our data. Variant chr2-189075416-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136935.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 = 0.0184 (2803/152270) while in subpopulation NFE AF = 0.0286 (1948/67994). AF 95% confidence interval is 0.0276. There are 33 homozygotes in GnomAd4. There are 1279 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2803 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.1081A>C	p.Met361Leu	missense	Exon 17 of 54	NP_000384.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.1081A>C	p.Met361Leu	missense	Exon 17 of 54	ENSP00000364000.3
	COL5A2	ENST00000858728.1		c.1078A>C	p.Met360Leu	missense	Exon 17 of 54	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.1081A>C	p.Met361Leu	missense	Exon 17 of 53	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2805 AN: 152152 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0184 AC: 4629 AN: 251122 AF XY: 0.0192

Gnomad AFR exome AF: 0.00413

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0217

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00804

Gnomad NFE exome AF: 0.0289

Gnomad OTH exome AF: 0.0242

GnomAD4 exome AF: 0.0259 AC: 37645 AN: 1453262 Hom.: 535 Cov.: 27 AF XY: 0.0256 AC XY: 18523 AN XY: 723470

African (AFR) AF: 0.00487 AC: 162 AN: 33290

American (AMR) AF: 0.0127 AC: 567 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0218 AC: 567 AN: 26024

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39534

South Asian (SAS) AF: 0.0102 AC: 877 AN: 85968

European-Finnish (FIN) AF: 0.00883 AC: 471 AN: 53326

Middle Eastern (MID) AF: 0.0383 AC: 220 AN: 5746

European-Non Finnish (NFE) AF: 0.0301 AC: 33303 AN: 1104642

Other (OTH) AF: 0.0246 AC: 1476 AN: 60060

GnomAD4 genome AF: 0.0184 AC: 2803 AN: 152270 Hom.: 33 Cov.: 32 AF XY: 0.0172 AC XY: 1279 AN XY: 74464

African (AFR) AF: 0.00604 AC: 251 AN: 41566

American (AMR) AF: 0.0210 AC: 321 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4824

European-Finnish (FIN) AF: 0.00819 AC: 87 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0286 AC: 1948 AN: 67994

Other (OTH) AF: 0.0242 AC: 51 AN: 2110

Alfa AF: 0.0251 Hom.: 189

Bravo AF: 0.0188

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0281 AC: 242

ExAC AF: 0.0183 AC: 2217

Asia WGS AF: 0.00491 AC: 17 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	-0.50	N
PhyloP100		4.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.27
Sift	Benign	0.80	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.39		Loss of MoRF binding (P = 0.1233)
MPC		0.48
ClinPred		0.025	T
GERP RS		5.2
Varity_R		0.25
gMVP		0.57
Mutation Taster		=98/2	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: rs76148000; hg19: chr2-189940142;