13-110424850-G-A

Variant names:

• chr13-110424850-G-A
• rs4238272
• NM_001846.4:c.297G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001846.4(COL4A2):​c.297G>A​(p.Thr99Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.961 in 1,614,068 control chromosomes in the GnomAD database, including 745,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67054 hom., cov: 31)
  • Exomes 𝑓: 0.96 (678191 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.795
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 13-110424850-G-A is Benign according to our data. Variant chr13-110424850-G-A is described in ClinVar as Benign. ClinVar VariationId is 311096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.795 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.297G>A	p.Thr99Thr	synonymous	Exon 5 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.297G>A	p.Thr99Thr	synonymous	Exon 5 of 48	ENSP00000353654.5	P08572
	COL4A2	ENST00000714399.1		c.297G>A	p.Thr99Thr	synonymous	Exon 5 of 49	ENSP00000519666.1	A0AAQ5BHW7
	COL4A2	ENST00000400163.8	TSL:5	c.297G>A	p.Thr99Thr	synonymous	Exon 5 of 48	ENSP00000383027.4	P08572

Frequencies

GnomAD3 genomes AF: 0.937 AC: 142587 AN: 152124 Hom.: 67015 Cov.: 31

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.985

Gnomad AMR AF: 0.964

Gnomad ASJ AF: 0.979

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.973

Gnomad FIN AF: 0.987

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.961

Gnomad OTH AF: 0.950

GnomAD2 exomes AF: 0.964 AC: 240599 AN: 249490 AF XY: 0.965

Gnomad AFR exome AF: 0.854

Gnomad AMR exome AF: 0.981

Gnomad ASJ exome AF: 0.981

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.985

Gnomad NFE exome AF: 0.961

Gnomad OTH exome AF: 0.971

GnomAD4 exome AF: 0.963 AC: 1407681 AN: 1461826 Hom.: 678191 Cov.: 50 AF XY: 0.963 AC XY: 700486 AN XY: 727218

African (AFR) AF: 0.851 AC: 28476 AN: 33474

American (AMR) AF: 0.981 AC: 43866 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.981 AC: 25635 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39695 AN: 39700

South Asian (SAS) AF: 0.971 AC: 83791 AN: 86254

European-Finnish (FIN) AF: 0.984 AC: 52559 AN: 53414

Middle Eastern (MID) AF: 0.959 AC: 5531 AN: 5768

European-Non Finnish (NFE) AF: 0.962 AC: 1070203 AN: 1111968

Other (OTH) AF: 0.959 AC: 57925 AN: 60394

GnomAD4 genome AF: 0.937 AC: 142684 AN: 152242 Hom.: 67054 Cov.: 31 AF XY: 0.938 AC XY: 69838 AN XY: 74430

African (AFR) AF: 0.859 AC: 35675 AN: 41542

American (AMR) AF: 0.964 AC: 14759 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.979 AC: 3399 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5149 AN: 5152

South Asian (SAS) AF: 0.973 AC: 4695 AN: 4824

European-Finnish (FIN) AF: 0.987 AC: 10484 AN: 10618

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.961 AC: 65339 AN: 68014

Other (OTH) AF: 0.950 AC: 2003 AN: 2108

Alfa AF: 0.950 Hom.: 60425

Bravo AF: 0.934

Asia WGS AF: 0.977 AC: 3397 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Porencephaly 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.090
DANN	Benign	0.66
PhyloP100		-0.80
PromoterAI		-0.0043	Neutral
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: rs4238272; hg19: chr13-111077197; COSMIC: COSV108196709; COSMIC: COSV108196709;