NM_001846.4:c.3454+164G>C

Variant names:

• chr13-110491504-G-C
• rs402661
• NM_001846.4:c.3454+164G>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.3454+164G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,182 control chromosomes in the GnomAD database, including 2,478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.18 (2478 hom., cov: 33)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.513
• Publications: 5 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 (BayesDel_noAF=-0.91).
• BP6: Variant 13-110491504-G-C is Benign according to our data. Variant chr13-110491504-G-C is described in ClinVar as Benign. ClinVar VariationId is 1229648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 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.3454+164G>C		intron	N/A	NP_001837.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.3454+164G>C		intron	N/A	ENSP00000353654.5
	COL4A2	ENST00000714399.1		c.3535+164G>C		intron	N/A	ENSP00000519666.1
	COL4A2	ENST00000400163.8	TSL:5	c.3454+164G>C		intron	N/A	ENSP00000383027.4

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27016 AN: 152064 Hom.: 2474 Cov.: 33

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.159

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.178 AC: 27043 AN: 152182 Hom.: 2478 Cov.: 33 AF XY: 0.184 AC XY: 13688 AN XY: 74388

African (AFR) AF: 0.155 AC: 6431 AN: 41522

American (AMR) AF: 0.169 AC: 2588 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 653 AN: 3470

East Asian (EAS) AF: 0.342 AC: 1765 AN: 5166

South Asian (SAS) AF: 0.269 AC: 1298 AN: 4826

European-Finnish (FIN) AF: 0.234 AC: 2477 AN: 10572

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11271 AN: 68008

Other (OTH) AF: 0.160 AC: 339 AN: 2116

Alfa AF: 0.175 Hom.: 305

Bravo AF: 0.169

Asia WGS AF: 0.265 AC: 920 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.43
PhyloP100		0.51
Mutation Taster		=100/0	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: rs402661; hg19: chr13-111143851; COSMIC: COSV64630522;