Genetic Variant COL5A2:p.Ala770Thr (chr2-189057349-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000393.5(COL5A2):c.2308G>A(p.Ala770Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,208 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A770S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.81

Publications

0 publications found

Variant links:

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

COL5A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL5A2	NM_000393.5 link	c.2308G>A	p.Ala770Thr	missense_variant	Exon 34 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4 link	c.2170G>A	p.Ala724Thr	missense_variant	Exon 37 of 57		XP_011508875.1
COL5A2	XM_047443251.1 link	c.2170G>A	p.Ala724Thr	missense_variant	Exon 39 of 59		XP_047299207.1
COL5A2	XM_047443252.1 link	c.2170G>A	p.Ala724Thr	missense_variant	Exon 38 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL5A2	ENST00000374866.9 link	c.2308G>A	p.Ala770Thr	missense_variant	Exon 34 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1 link	c.1147G>A	p.Ala383Thr	missense_variant	Exon 27 of 47	5		ENSP00000482184.1
COL5A2	ENST00000470524.2 link	n.414G>A		non_coding_transcript_exon_variant	Exon 7 of 8	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725542

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1109020

Other (OTH)

AF:

0.00

AC:

AN:

60220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.0

.;D;D

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

0.71

N;.;N

PhyloP100

4.8

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.9

N;.;.

REVEL

Uncertain

0.36

Sift

Benign

0.065

T;.;.

Sift4G

Uncertain

0.048

D;T;.

Vest4

0.41

ClinPred

0.80

GERP RS

5.9

Varity_R

0.095

gMVP

0.11

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over