chr13-110469223-A-G

Variant names:

• chr13-110469223-A-G
• rs78829338
• NM_001846.4:c.2102A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001846.4(COL4A2):​c.2102A>G​(p.Lys701Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00495 in 1,591,600 control chromosomes in the GnomAD database, including 331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (288 hom.)
• Consequence: COL4A2 NM_001846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.29
• Publications: 10 publications found

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]

COL4A2 Gene-Disease associations (from GenCC):

• porencephaly 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• COL4A1 or COL4A2-related cerebral small vessel disease

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040277243).
• BP6: Variant 13-110469223-A-G is Benign according to our data. Variant chr13-110469223-A-G is described in ClinVar as Benign. ClinVar VariationId is 235684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.2102A>G	p.Lys701Arg	missense	Exon 28 of 48	NP_001837.2	P08572

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.2102A>G	p.Lys701Arg	missense	Exon 28 of 48	ENSP00000353654.5	P08572
	COL4A2	ENST00000714399.1		c.2183A>G	p.Lys728Arg	missense	Exon 29 of 49	ENSP00000519666.1	A0AAQ5BHW7
	COL4A2	ENST00000400163.8	TSL:5	c.2102A>G	p.Lys701Arg	missense	Exon 28 of 48	ENSP00000383027.4	P08572

Frequencies

GnomAD3 genomes AF: 0.00860 AC: 1309 AN: 152122 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0602

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.0190 AC: 3994 AN: 210576 AF XY: 0.0156

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.00316

Gnomad EAS exome AF: 0.0145

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.000549

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.00456 AC: 6563 AN: 1439360 Hom.: 288 Cov.: 31 AF XY: 0.00428 AC XY: 3053 AN XY: 713512

African (AFR) AF: 0.00124 AC: 41 AN: 33192

American (AMR) AF: 0.104 AC: 4309 AN: 41330

Ashkenazi Jewish (ASJ) AF: 0.00313 AC: 80 AN: 25588

East Asian (EAS) AF: 0.0180 AC: 703 AN: 39108

South Asian (SAS) AF: 0.00294 AC: 242 AN: 82230

European-Finnish (FIN) AF: 0.0115 AC: 597 AN: 51978

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5742

European-Non Finnish (NFE) AF: 0.000302 AC: 332 AN: 1100662

Other (OTH) AF: 0.00423 AC: 252 AN: 59530

GnomAD4 genome AF: 0.00866 AC: 1319 AN: 152240 Hom.: 43 Cov.: 32 AF XY: 0.00974 AC XY: 725 AN XY: 74448

African (AFR) AF: 0.00173 AC: 72 AN: 41536

American (AMR) AF: 0.0609 AC: 931 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3466

East Asian (EAS) AF: 0.0164 AC: 85 AN: 5176

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4824

European-Finnish (FIN) AF: 0.0139 AC: 148 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68022

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00492 Hom.: 92

Bravo AF: 0.0138

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000780 AC: 3

ESP6500EA AF: 0.000607 AC: 5

ExAC AF: 0.0123 AC: 1473

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Porencephaly 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0040	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	-0.010	N
PhyloP100		4.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.33
Sift	Benign	0.40	T
Sift4G	Benign	0.31	T
Polyphen		0.96	D
Vest4		0.045
MPC		0.37
ClinPred		0.038	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.30
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs78829338; hg19: chr13-111121570; COSMIC: COSV64628211;