rs148220961

Positions:

• chr2-189098775-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000393.5(COL5A2):​c.370-16C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,609,678 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (70 hom.)
• Consequence: COL5A2 NM_000393.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.299

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-189098775-G-A is Benign according to our data. Variant chr2-189098775-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189098775-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0073 (1112/152254) while in subpopulation AMR AF= 0.0172 (263/15286). AF 95% confidence interval is 0.0155. There are 8 homozygotes in gnomad4. There are 523 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.370-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.232-16C>T		splice_polypyrimidine_tract_variant, intron_variant			XP_011508875.1
COL5A2	XM_047443251.1	c.232-16C>T		splice_polypyrimidine_tract_variant, intron_variant			XP_047299207.1
COL5A2	XM_047443252.1	c.232-16C>T		splice_polypyrimidine_tract_variant, intron_variant			XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.370-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000393.5	ENSP00000364000	P1
COL5A2	ENST00000618828.1	c.-261-16C>T		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000482184
COL5A2	ENST00000649966.1	c.232-16C>T		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000496785

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1114 AN: 152136 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00838

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00737 AC: 1848 AN: 250852 Hom.: 11 AF XY: 0.00719 AC XY: 975 AN XY: 135624

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.0346

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000652

Gnomad NFE exome AF: 0.00839

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.00755 AC: 11003 AN: 1457424 Hom.: 70 Cov.: 28 AF XY: 0.00739 AC XY: 5363 AN XY: 725314

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0342

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.000677

Gnomad4 NFE exome AF: 0.00792

Gnomad4 OTH exome AF: 0.00829

GnomAD4 genome AF: 0.00730 AC: 1112 AN: 152254 Hom.: 8 Cov.: 33 AF XY: 0.00702 AC XY: 523 AN XY: 74452

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00838

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00980 Hom.: 2

Bravo AF: 0.00826

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2017	Variant summary: The COL5A2 c.370-16C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing while ESE finder predicts the loss of a SRp40 binding motif. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been observed in a large, broad control population, ExAC, in 762/119346 control chromosomes (2 homozygotes) at a frequency of 0.0063848, which is approximately 1022 times the estimated maximal expected allele frequency of a pathogenic COL5A2 variant (0.0000063), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Ehlers-Danlos syndrome, classic type, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 10, 2023

- -

Ehlers-Danlos syndrome, classic type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.7
DANN	Benign	0.78

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

LitVar

Other links and lift over

dbSNP: rs148220961; hg19: chr2-189963501;