NM_000393.5:c.3169A>G

Variant names:

• chr2-189048241-T-C
• rs768663426
• NM_000393.5:c.3169A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000393.5(COL5A2):​c.3169A>G​(p.Thr1057Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1057N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.852
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.120990515).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000889 (13/1461732) while in subpopulation MID AF = 0.000173 (1/5766). AF 95% confidence interval is 0.0000298. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 13 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.3169A>G	p.Thr1057Ala	missense	Exon 45 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.3169A>G	p.Thr1057Ala	missense	Exon 45 of 54	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.3166A>G	p.Thr1056Ala	missense	Exon 45 of 54	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.3169A>G	p.Thr1057Ala	missense	Exon 45 of 53	ENSP00000528788.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251302 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461732 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727180

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.0000894 AC: 4 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111932

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.085	N
PhyloP100		0.85
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.29
Sift	Benign	0.33	T
Sift4G	Benign	0.51	T
Polyphen		0.011	B
Vest4		0.39
MutPred		0.24		Loss of phosphorylation at T1057 (P = 0.0038)
MVP		0.50
MPC		0.25
ClinPred		0.17	T
GERP RS		5.4
Varity_R		0.050
gMVP		0.090
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs768663426; hg19: chr2-189912967;