chr2-189179604-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PVS1_SupportingPM2BS1

The NM_000393.5(COL5A2):c.1A>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

COL5A2
NM_000393.5 initiator_codon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.455

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: Likely_benign. The variant received -1 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 2 codons. Genomic position: 189179601. Lost 0.001 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000138 (2/1449812) while in subpopulation AFR AF = 0.00006 (2/33338). AF 95% confidence interval is 0.00000994. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL5A2	NM_000393.5 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4 link	c.-42+45544A>T		intron_variant	Intron 4 of 56		XP_011508875.1
COL5A2	XM_047443251.1 link	c.-42+45544A>T		intron_variant	Intron 6 of 58		XP_047299207.1
COL5A2	XM_047443252.1 link	c.-42+45544A>T		intron_variant	Intron 5 of 57		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL5A2	ENST00000374866.9 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1 link	c.-630A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 47	5		ENSP00000482184.1
COL5A2	ENST00000618828.1 link	c.-630A>T		5_prime_UTR_variant	Exon 1 of 47	5		ENSP00000482184.1
COL5A2	ENST00000649966.1 link	c.-42+45544A>T		intron_variant	Intron 1 of 10			ENSP00000496785.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449812

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720054

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33338

American (AMR)

AF:

0.00

AC:

AN:

43842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25630

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

84572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104508

Other (OTH)

AF:

0.00

AC:

AN:

59892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Benign

-0.64

PhyloP100

0.46

PROVEAN

Benign

-0.20

N;.

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.0

B;B

Vest4

0.74

MutPred

0.98

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.97

ClinPred

0.93

GERP RS

2.5

PromoterAI

-0.17

Neutral

(source)

Varity_R

0.76

gMVP

0.71

Mutation Taster

=81/19

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