rs62621875

chr13-110491334-C-Achr13-110491334-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001846.4(COL4A2):c.3448C>A(p.Gln1150Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00159 in 1,580,738 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (18 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (10 hom.)
• Consequence: COL4A2 NM_001846.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 4.29

Genes affected

COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001846.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.006136745).
• BP6: Variant 13-110491334-C-A is Benign according to our data. Variant chr13-110491334-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 29630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00806 (1228/152274) while in subpopulation AFR AF= 0.0274 (1137/41548). AF 95% confidence interval is 0.026. There are 18 homozygotes in gnomad4. There are 575 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4	c.3448C>A	p.Gln1150Lys	missense_variant	37/48	ENST00000360467.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7	c.3448C>A	p.Gln1150Lys	missense_variant	37/48	5	NM_001846.4	P1
COL4A2	ENST00000650225.1	n.1103C>A		non_coding_transcript_exon_variant	8/19

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1225 AN: 152156 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00176 AC: 343 AN: 194902 Hom.: 3 AF XY: 0.00145 AC XY: 152 AN XY: 104922

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000395

Gnomad FIN exome AF: 0.0000571

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.000903 AC: 1290 AN: 1428464 Hom.: 10 Cov.: 30 AF XY: 0.000817 AC XY: 578 AN XY: 707570

Gnomad4 AFR exome AF: 0.0255

Gnomad4 AMR exome AF: 0.00213

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000610

Gnomad4 FIN exome AF: 0.000156

Gnomad4 NFE exome AF: 0.000205

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00806 AC: 1228 AN: 152274 Hom.: 18 Cov.: 33 AF XY: 0.00772 AC XY: 575 AN XY: 74462

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00159 Hom.: 5

Bravo AF: 0.00958

ESP6500AA AF: 0.0196 AC: 78

ESP6500EA AF: 0.000481 AC: 4

ExAC AF: 0.00192 AC: 230

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Porencephaly 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	COL4A2: BP4 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

COL4A2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Porencephaly 2;C3281105:Hemorrhage, intracerebral, susceptibility to Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 13, 2021

- -

Hemorrhage, intracerebral, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 13, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.090
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.38	N
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	0.33	T
Sift4G	Benign	0.90	T
Polyphen		0.98	D
Vest4		0.86
MVP		0.68
MPC		0.48
ClinPred		0.026	T
GERP RS		5.0
Varity_R		0.25
gMVP		0.67

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: rs62621875; hg19: chr13-111143681;