13-110467049-G-C

Variant names:

• chr13-110467049-G-C
• rs3803230
• NM_001846.4:c.2048G>C

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.2048G>C​(p.Gly683Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,708 control chromosomes in the GnomAD database, including 8,862 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (838 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8024 hom.)
• Consequence: COL4A2 NM_001846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.651
• Publications: 26 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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=0.0043233335).
• BP6: Variant 13-110467049-G-C is Benign according to our data. Variant chr13-110467049-G-C is described in ClinVar as Benign. ClinVar VariationId is 311143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.2048G>C	p.Gly683Ala	missense	Exon 27 of 48	NP_001837.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.2048G>C	p.Gly683Ala	missense	Exon 27 of 48	ENSP00000353654.5
	COL4A2	ENST00000714399.1		c.2129G>C	p.Gly710Ala	missense	Exon 28 of 49	ENSP00000519666.1
	COL4A2	ENST00000400163.8	TSL:5	c.2048G>C	p.Gly683Ala	missense	Exon 27 of 48	ENSP00000383027.4

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15518 AN: 151966 Hom.: 838 Cov.: 32

Gnomad AFR AF: 0.0948

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0772

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.108 AC: 26931 AN: 249322 AF XY: 0.108

Gnomad AFR exome AF: 0.0962

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.128

Gnomad FIN exome AF: 0.0769

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.103 AC: 150748 AN: 1461624 Hom.: 8024 Cov.: 32 AF XY: 0.103 AC XY: 75211 AN XY: 727110

African (AFR) AF: 0.0988 AC: 3308 AN: 33472

American (AMR) AF: 0.118 AC: 5274 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3755 AN: 26116

East Asian (EAS) AF: 0.0843 AC: 3344 AN: 39686

South Asian (SAS) AF: 0.109 AC: 9408 AN: 86246

European-Finnish (FIN) AF: 0.0731 AC: 3904 AN: 53382

Middle Eastern (MID) AF: 0.160 AC: 925 AN: 5766

European-Non Finnish (NFE) AF: 0.103 AC: 114194 AN: 1111888

Other (OTH) AF: 0.110 AC: 6636 AN: 60378

GnomAD4 genome AF: 0.102 AC: 15525 AN: 152084 Hom.: 838 Cov.: 32 AF XY: 0.101 AC XY: 7510 AN XY: 74348

African (AFR) AF: 0.0949 AC: 3936 AN: 41482

American (AMR) AF: 0.109 AC: 1664 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3468

East Asian (EAS) AF: 0.108 AC: 559 AN: 5158

South Asian (SAS) AF: 0.100 AC: 483 AN: 4816

European-Finnish (FIN) AF: 0.0772 AC: 816 AN: 10572

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.106 AC: 7196 AN: 67990

Other (OTH) AF: 0.119 AC: 251 AN: 2106

Alfa AF: 0.110 Hom.: 711

Bravo AF: 0.107

TwinsUK AF: 0.107 AC: 397

ALSPAC AF: 0.108 AC: 418

ESP6500AA AF: 0.0960 AC: 372

ESP6500EA AF: 0.107 AC: 883

ExAC AF: 0.106 AC: 12809

Asia WGS AF: 0.101 AC: 352 AN: 3478

EpiCase AF: 0.114

EpiControl AF: 0.115

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Porencephaly 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.80
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.65
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.28
Sift	Benign	0.44	T
Sift4G	Benign	0.25	T
Polyphen		0.0030	B
Vest4		0.051
MPC		0.73
ClinPred		0.0027	T
GERP RS		1.4
PromoterAI		0.024	Neutral
Varity_R		0.032
gMVP		0.25
Mutation Taster		=98/2	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: rs3803230; hg19: chr13-111119396; COSMIC: COSV64628379; COSMIC: COSV64628379;