rs201105747

chr13-110512120-G-Achr13-110512120-G-T

Variant summary

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

The NM_001846.4(COL4A2):c.5068G>A(p.Ala1690Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00046 in 1,613,472 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1690A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: COL4A2 NM_001846.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.858

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009438992).
• BP6: Variant 13-110512120-G-A is Benign according to our data. Variant chr13-110512120-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 29631.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 = 0.00141 (215/152312) while in subpopulation AFR AF= 0.00457 (190/41572). AF 95% confidence interval is 0.00404. There are 0 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 215 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4	c.5068G>A	p.Ala1690Thr	missense_variant	48/48	ENST00000360467.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7	c.5068G>A	p.Ala1690Thr	missense_variant	48/48	5	NM_001846.4	P1
COL4A2	ENST00000463084.1	n.666G>A		non_coding_transcript_exon_variant	3/3	3
COL4A2	ENST00000648222.1	n.756G>A		non_coding_transcript_exon_variant	1/1
COL4A2	ENST00000650225.1	n.2723G>A		non_coding_transcript_exon_variant	19/19

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000490 AC: 122 AN: 248884 Hom.: 0 AF XY: 0.000362 AC XY: 49 AN XY: 135258

Gnomad AFR exome AF: 0.00479

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00212

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000361 AC: 528 AN: 1461160 Hom.: 4 Cov.: 34 AF XY: 0.000345 AC XY: 251 AN XY: 726894

Gnomad4 AFR exome AF: 0.00502

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00763

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74488

Gnomad4 AFR AF: 0.00457

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000345 Hom.: 1

Bravo AF: 0.00158

ESP6500AA AF: 0.00429 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000537 AC: 65

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Porencephaly 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	COL4A2: BS1, BS2 -

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	0.19
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.017	D
Sift4G	Benign	0.14	T
Polyphen		0.95	P
Vest4		0.17
MVP		0.94
MPC		0.29
ClinPred		0.022	T
GERP RS		4.0
Varity_R		0.14
gMVP		0.61

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: rs201105747; hg19: chr13-111164467; COSMIC: COSV64628588; COSMIC: COSV64628588;